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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.1  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.

Hypoglycaemia is a Family Affair

Hypoglycaemia affects not only people with diabetes, but everyone who loves and cares for them. Having a brother with type 1 diabetes, I have seen this phenomenon up close. My brother would sometimes drive to unfamiliar places without remembering how he got there. He would awaken at night, confused and belligerent. On several occasions, a family member had to call emergency medical services to treat him. Over time, these episodes created a chronic weariness and wariness in our family, which persisted even after a continuous glucose monitoring (CGM) system significantly reduced his lows. Having a sister who knows quite a lot about hypoglycaemia has not fully solved his challenges with hypoglycaemia.

Our family is hardly alone. In one survey of families of people with diabetes, 85% of respondents reported being at least occasionally worried about the risk of hypoglycaemia.1 Family members may be afraid and anxious to leave the person with diabetes alone or in the care of others. Their fear may surge every time the person gets behind a steering wheel – especially if hypoglycaemia awareness is compromised. Family members may also fear for their own safety, as hypoglycaemia may lead individuals to become aggressive and combative.2

Needless to say, such worries increase the burden on family members.3 In the above-mentioned survey, family worry was associated with frustration and diabetes-related arguments.1 Other research has found that family members become resentful and neglect their own health,2 and the threat of nocturnal hypoglycaemia is liable to disrupt their sleep. Even new technologies that reduce this threat, such as CGM with glucose suspend, may lead some caregivers to toss and turn at night as they listen for the dreaded low-glucose alarm.

By the same token, a family’s coping style has a profound impact on the affected individual’s capacity to manage the disease. Studies of families affected by diabetes have confirmed that family cohesion and low family conflict correlate with the capacity to adapt to diabetes and adhere to treatment.3  For married couples, the quality of the marriage appears to have a similar impact.4

While family members are often the first to recognize impending or actual hypoglycaemia, they may overestimate their capacity to deal with the problem and fail to recognize when they need help.2 That’s why it’s important to include family members/caregivers in hypoglycaemia assessments. At the very minimum, all individuals with diabetes at significant risk of hypoglycaemia (i.e., those in insulin, sulfonylureas or glitinides) should have a hypoglycaemia detection and treatment plan that includes family members.

Discussions with families can also help identify poor coping styles, knowledge gaps, and disproportionate fears. Some suggestions to keep in mind:

  • Ask family members about the frequency and symptoms of hypoglycaemia in the affected individual.
  • Inquire about their fears and concerns, and acknowledge that many other people share those fears.
  • Ensure family members are comfortable administering hypoglycaemia treatment, including glucagon, and know when/where to call for emergency services.
  • If you have reason to suspect family conflict, refer the family to a therapist.

Interest in the impact of hypoglycaemia on family members is growing. It is our hope that future research will identify interventions to reduce the burden of hypoglycaemia on family systems.

No less important, of course, is to reduce the risk of hypoglycaemia in the first place. That’s the approach my brother and his family took when his daughter was diagnosed with type 1 diabetes at age 23. Having seen the ripple effect of her father’s severe hypoglycaemia, she did not want to go down the same road. Thanks to new insulins and treatments, she has largely avoided this fate. And our whole family is breathing more easily.

References

  1. Nef G et al. Correlates and outcomes of worries about hypoglycemia in family members of adults with diabetes: The second Diabetes Attitudes, Wishes and Needs (DAWN2) study. J Psychosom Res 2016; 89:69-77.
  2. Lawton J et al. Experiences, Views, and Support Needs of Family Members of People With Hypoglycemia Unawareness: Interview Study. Diabetes Care 2014; 37:109-115.
  3. Nefs G, Pouwer F. The role of hypoglycemia in the burden of living with diabetes among adults with diabetes and family members: results from the DAWN2 study in The Netherlands. BMC Public Health 2018;18:156.
  4. Trief P et al. The marital relationship and psychosocial adaptation and glycemic control of individuals with diabetes. Diabetes Care 2001; 24:1384-89.

Severe Hypoglycaemia in Children: A Shifting Landscape

Many clinicians perceive the risk of severe hypoglycaemia as firmly tethered to the level of glucose control: the tighter the control, the greater the risk. This perception has its roots in the historical association between A1C and hypoglycaemia risk, established in several studies. As a frequently cited example, the DCCT trial found a 3-fold increased risk of severe hypoglycaemia in patients randomized to the intensive management arm of the study.1

In recent years, however, researchers have noted a weakening of this association, both in adults and in children. Notably, a 2017 cross-sectional analysis of three contemporary pediatric diabetes registries found no association between severe hypoglycaemia rates and HbA1c.2 Using data from pediatric (< 18 years old) patients with type 1 diabetes for at least 2 years, the analysis found that HbA1c had no significant bearing on the rate of severe hypoglycaemia, whether examined by source registry, treatment regimen, or age group. Importantly, the lack of association prevailed in both patients treated with insulin injections and those treated with continuous subcutaneous insulin infusion (CSII).

Other studies have reported similar trends, but this analysis stands out in its use of data from multiple prospective diabetes registries. Further, subjects were receiving “usual care” in a variety of clinical settings, thus reflecting real-world practice more faithfully than subjects in randomized clinical trials such as DCCT.

Of course, confounding factors may have biased the results. For example, after experiencing a severe hypoglycaemia event, fear of hypoglycaemia may have led some patients to relax their glycaemic control, thereby raising HbA1c.

While further investigation is recommended to corroborate the study’s findings, these findings are nonetheless encouraging. It stands to reason that advances in treatment, such as the use of insulin analogues, CSII, increased frequency of glucose monitoring, continuous glucose monitoring (CGM), and overall better management approaches may be enabling better glycaemic control without a corresponding increase in hypoglycaemia risk.

The historical relationship between glycaemic control lower glycemic control and risk of severe hypoglycemia has understandably contributed to a fear of hypoglycaemia in patients and their caregivers and stood as an obstacle to optimal glycaemic control.3 The weakening, if not disappearance, of the relationship gives new hope to children with type 1 diabetes.

New era, new definitions

In a parallel development, multiple studies have uncovered a reduction in hypoglycaemic coma and convulsion in children in recent years. This shift has led researchers to revisit the established definition of severe hypoglycaemia in children, which puts an emphasis on coma and convulsion.  Recognizing the need for an update in hypoglycaemia classification, the International Society for Pediatric and Adolescent Diabetes (ISPAD) has proposed definitions that align with the IHSG classification system.4 Namely:

  • Clinical hypoglycemia alert: A glucose value of ≤3.9 mmol/L (70 mg/dL) can be used as a threshold or “alert” value to prevent hypoglycaemia.
  • Clinically important or serious hypoglycaemia: A glucose value of <3.0 mmol/L (54 mg/dL) indicates clinically significant hypoglycaemia that may cause defective glucose counter-regulation and impaired awareness of hypoglycaemia (IAH), with an attendant increase in severe hypoglycaemia risk.5
  • Severe hypoglycemia: This refers to an event requiring another person to take corrective action, in alignment with the (adult) definition in the ADA guidelines.6 Given that children sometimes require external assistance for milder hypoglycaemia, caregiver assessment and judgment are required to make the distinction.

While no single glucose level can define hypoglycaemia for all patients, standardized definitions (such as the above) allow comparisons between models of care. In individual patients, keeping careful records of hypoglycaemic events—and possible precipitants—enables clinicians to establish patterns and take corrective action to minimize the risk of severe events. While such events are still too common, modern treatment and educational approaches can significantly reduce their frequency.

References

  1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993;329:977-986.
  2. Haynes A et al. Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases. Pediatr Diabetes. 2017;18:643–650.
  3. Frier BM. Hypoglycemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol 2014;10:711-722.
  4. Jones TW. Defining relevant hypoglycemia measures in children and adolescents with type 1 diabetes. Pediatric Diabetes. 2017;1–2.
  5. Davis MR, Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metabol 1991;73:995–1001.
  6. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384–1395.

Can Patients Rely On Their Blood Glucose Readings?

Optimizing glucose control is critical for patients with diabetes to minimize risks of micro- and macrovascular complications associated with hyperglycaemia. To this end, individuals with diabetes who depend on insulin replacement therapy, particularly those on basal-bolus regimens, need to be aware of their blood glucose values to guide treatment decisions.

In recent years, continuous or semi-continuous glucose monitoring devices have become available and are increasingly adopted in clinical care. Nevertheless, most patients still rely on self-monitoring of blood glucose (SMBG), which typically involves measuring the glucose concentration in a drop of blood taken from the fingertip, using a glucose meter or glucose strips.  This introduces a range of potential errors that could impact on the reliability of the reading. It should be remembered that reliability of glucose readings can be divided into two components: accuracy and precision. Accuracy refers to how closely a reading matches the laboratory reference value, while precision denotes the degree of reproducibility in multiple readings.

It has been estimated that 90% of deviant glucose readings are “operator dependent.” The blood sample may be too small for some meters to record or properly report the error.2 The patient may have anaemia, which could affect the reading in glucose meters that assume normal haematocrit in their calculations. Deviations of up to 20% may occur when blood is taken from the forearm and thigh, rather than the fingertip.3 Taking measurements at extreme temperatures may likewise skew the results. Although rare, acetaminophen, ascorbic acid and mannitol can impact readings from meters that use the glucose oxidase method. Glucose strips, if used, may lose accuracy when exposed to light or moisture.

Such circumstantial errors aside, hand-held instruments do not equate to clinician-grade laboratory instruments. This is why SMBG cannot be used to diagnose diabetes, particularly type 2. Some glucose meters do not adequately sense hypoglycaemia, particularly for asymptomatic events in the ICU setting.4,5 Of note, glucose meters that err on the side of underreporting glucose values are associated with a higher HbA1c than those that deviate in the other direction.6

There are literally dozens of glucose meters available. For market introduction, at least in Europe and the US, glucose meters need to comply with the new ISO15197:2013 standard for SMBG systems.1 This standard states that accuracy should be within 15% at glucose values > 4.2 mmol/L (75 mg/dL) and within ≤ 0.8 mmol/L for lower glucose values, for 99% of all results. This is considerably more stringent than the 2003 standard, which allowed an accuracy error of no more than 20% in at least 95% of measurements. That said, even glucose meters that meet the current standard may differ considerably in accuracy and precision, with clinically significant consequences around the boundary of hypoglycaemia.

For example, a value of 3.2 mmol/L can vary between 2.4 and 4.0 mmol/L without falling outside the ISO standard’s accuracy limits. Such deviations may lead patients to miscalculate the amount of insulin they actually require. A bias of just 10% can lead patients to misdose their insulin by 2 units in half of cases.7 If they overestimate their insulin requirements, they may tip into the hypoglycaemic range.

Proper patient education can help minimize, if not fully eliminate, such risks. Helpful SMBG strategies include:

  • Always using the same glucose meter
  • Washing hands with water and soap (not alcohol) prior to taking a reading
  • If hand washing is not feasible, wipe off the first drop of blood and use the second drop of blood
  • In extreme weather conditions, wearing glucose meters close to the body and conducting measurements indoors, if possible
  • Using modern glucose meters that make quick measurements that can be electronically converted to bolus insulin calculations

Finally, although continuous glucose monitoring or flash glucose monitoring have many benefits over SMBG, it should be acknowledged that they may be less reliable in the extremes of the glucose spectrum. This means that patients are advised to always check a low or (extremely) high glucose value reported by such a device with a SMBG.

References

  1. ISO 15197:2013. Accessed Nov. 12, 2017 at https://www.iso.org/standard/54976.html
  2. Pfützner A et al. Evaluation of the effects of insufficient blood volume samples on the performance of blood glucose self-test meters. Diab Sci Technol 2013;7:1522.
  3. Bina DM et al. Clinical impact of prandial state, exercise, and site preparation on the equivalence of alternative-site blood glucose testing. Diabetes Care 2003;26:981-5.
  4. Sonmez A et al. The accuracy of home glucose meters. Diab Tech Ther 2010;12:619.
  5. Voulgari C et al. Accuracy and precision of glucose monitoring are relevant to treatment decision-making and clinical outcome in hospitalized patients with diabetes. Diab Tech Ther 2011;13:723.
  6. Boettcher C et al. Accuracy of blood glucose meters for self-monitoring affects glucose control and hypoglycemia rate in children and adolescents with type 1 diabetes. Diab Tech Ther 2015;17:275.
  7. Boyd JC, Bruns DE. Quality specifications for glucose meters: assessment by simulation modeling of errors in insulin dose. Clin Chem 2001;47:209-14

Giving Severe Hypoglycaemia the Attention it is Due

There is a line in the sand between mild and severe hypoglycaemia (SH). While mild hypoglycaemia is not trivial, it does not threaten life and health as SH does. For people who depend on insulin and other glucose-lowering drugs associated with hypoglycaemia, clinicians often consider a degree of SH “the cost of doing business” in diabetes management—in other words, an unwanted but unavoidable corollary of treatment. Such an attitude from diabetes professionals is misguided. We must regard SH more seriously and take every reasonable measure to protect patients from its consequences.

SH may be far more prevalent than previously suspected. In the Hypoglycemia Assessment Tool (HAT) study, a 24-country study of over 27,000 people with type 1 and type 2 diabetes (T1D and T2D) on insulin, self-reported rates of SH (defined as needing the help of another person for recovery) were about 5 times higher than those in previous population-based reports.1 In the study, insulin-treated subjects with T2D had an annual SH rate of 2.5 per patient.

Studies have linked SH to an increased risk of macrovascular events and cardiovascular death and found it to strongly predict all-cause mortality.2,3 A severe hypoglycaemic event was the strongest predictor of death at 90 days in the VADT trial,4 while a post-hoc analysis of the ADVANCE trial linked SH to a significant increase in the risk of death and major cardiovascular events.3

More recent evidence has corroborated this link. In the ORIGIN trial, designed to assess whether normalizing fasting plasma glucose could reduce cardiovascular events,5 SH had a bearing on the risk of the composite primary endpoint, which included cardiovascular death, myocardial infarction, and stroke.2,5 The DEVOTE study, which assessed the cardiovascular safety of insulin degludec vs glargine in T2D patients, yielded similar findings.6 DEVOTE also linked SH to a higher risk of short-term death.

The nature of the SH-cardiovascular link is unclear: it may arise from the direct effect of low glucose levels or from activation of the sympathoadrenal response, which not only increases cardiac workload but also induces a prothorombotic, inflammatory, arrhythmogenic state.7

Whatever the cause, the connection is real. The more we study SH, the more we appreciate its seriousness. We have strategies to reduce the risk, such as new-generation insulin analogues and the judicious use of technology. Perhaps the most important strategy of all is patient education. We need to ensure that patients have a better understanding of hypoglycaemia, learn to respect it and have the skills to minimize it, but without fearing it to the point of abandoning glycaemic treatment goals.

References

  1. Khunti K AS, Alsifri S, Aronson R, et al. Self-reported hypoglycaemia: a global study of 24 countries with 27,585 insulin-treated patients with diabetes: the HAT study. Diabetologia 2014; 57 Suppl:S201-202.
  2. Investigators OT, Mellbin LG, Ryden L, et al. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013; 34(40):3137-3144.
  3. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. The New England journal of medicine 2010; 363(15):1410-1418.
  4. Investigators V. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. The New England journal of medicine 2015; 373(10):978.
  5. Investigators OT. Gerstein HC, Bosch J, Dagenais GR, Diaz R, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. The New England journal of medicine 2012; 367(4):319-332.
  6. Pieber TR, Marso SP, McGuire DK, et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia 2017 Sept. 15; doi: 10.1007/s00125-017-4422-0.
     
    [Epub ahead of print].
  7. Hanefeld M, Frier BM, Pistrosch F: Hypoglycemia and Cardiovascular Risk: Is There a Major Link? Diabetes care 2016; 39 Suppl 2:S205-209.

Hypoglycaemic Mortality in Diabetes

Abstract

Iatrogenic hypoglycaemia is the limiting factor in the glycaemic management of diabetes, particularly with insulin. That hypoglycaemia can kill experimental animals has been known since the discovery of insulin. There are now numerous reports of deaths of patients with diabetes associated with hypoglycaemia. Since hypoglycaemia can kill, and hypoglycaemia at the time of death has been documented by continuous glucose monitoring in a patient with diabetes, it is reasonable to conclude that these are causal associations. That conclusion is supported by hypoglycaemia mortality rates of 7% to 10% or more in series of patients with diabetes. Given the lack of convincing evidence of clinically important outcomes that require intensive glycaemic control, it is difficult to justify tight glycaemic control in patients with diabetes who are at risk of harm from hypoglycaemia or who have no likelihood of benefit.

Iatrogenic hypoglycaemia is the limiting factor in the glycaemic management of diabetes with insulin, a sulfonylurea or a glinide (1). Hypoglycaemia is particularly common in patients whose diabetes is treated with insulin (2). Serious, clinically important hypoglycaemia (3) occurs frequently. For example, continuous glucose monitoring detected glucose concentrations less than 3.0 mmol/L (54 mg/dL) were found to occur every three or four days in a study of patients with type 1 diabetes mellitus (T1DM) using multiple daily injections of insulin (4).

That hypoglycaemia can kill has been known since the discovery of insulin in 1921. Collip and colleagues found that decrements in the blood glucose concentrations following injection of the pancreatic insulin extract into rabbits could be fatal and documented that death of the animals could be prevented by administration of glucose (5). Clinical colleagues of Banting and Best had patients with diabetes die from “hypoglycaemic reactions” (5).

There are now numerous reports of deaths associated with hypoglycaemia in patients with diabetes (e.g., 5-13). In addition to clinical hypoglycaemic death (5), the findings included: Increased mortality with severe (requiring the assistance of another person), symptomatic hypoglycaemia in type 2 diabetes mellitus (T2DM) (6), increased mortality with severe hypoglycaemia in patients with T2DM (7-9), increased cardiovascular and arrhythmic mortality with severe hypoglycaemia in insulin-treated patients with T2DM or impaired glucose tolerance (10), increased mortality with severe hypoglycaemia and seizure, coma, or both in type 1 diabetes mellitus (T1DM) (11), increased mortality in intensive care unit (ICU) patients with hypoglycaemia of less than 70 mg/dL (3.9 mmol/L) (12) and increased mortality in ICU patients and in hospital inpatients with hypoglycaemia of less than 70 mg/dL (3.9 mmol/L) (13). Given the fact that it is known that hypoglycaemia can kill experimental animals (5) and that hypoglycaemia was documented by continuous glucose monitoring at the time of death of a patient with T1DM (14), it is reasonable to conclude that these are causal associations.

Where reported (8,9) the risk of hypoglycaemia associated with death was stronger with shorter intervals between the detected episode of hypoglycaemia and death, consistent with a causal connection between hypoglycaemia and death. Obviously, the last detected episode of hypoglycaemia was not the cause of death since, in the absence of a continuous glucose monitoring record (14), the patient had to survive to report it. But, previous hypoglycaemia is a potent risk factor for subsequent, potentially fatal hypoglycaemia (1). The culprit is not the last detected episode of hypoglycaemia but rather a subsequent episode predicted by that last episode. The interval is not critical, although a shorter interval between the last detected episode and death suggests more frequent hypoglycaemia.

The conclusion that these are causal associations is supported by reports of hypoglycaemic mortality rates in series of patients with diabetes (11,15-19). Early reports indicated that 2% to 4% of deaths of patients with T1DM were the result of hypoglycaemia (15-17). However, more recent reports include hypoglycaemic mortality rates of 7% (18), 8% (11), and 10% (19) in childhood-onset (largely T1DM) diabetes. Indeed, the estimate of Skrivarhaug and colleagues (19) that 10% of deaths of Norwegian patients with childhood-onset T1DM were the result of hypoglycaemia may well have been an under estimate since another 15% of the deaths were listed as “sudden death” or “unexpected death,” categories in which the cause of death was ill-defined and might have been the result of hypoglycaemia and cardiac dysrhythmias as the authors suggested. One wonders if the higher hypoglycaemic mortality rates in the more recent reports (11,18,19) might be a clue to overtreatment of diabetes in recent years.

Primary brain death sometimes occurs in patients with diabetes who suffer prolonged, profound iatrogenic hypoglycaemia, but most hypoglycaemia mortality is probably the result of a fatal cardiac arrhythmia with secondary brain death. There is increasing evidence that hypoglycaemia is pro-arrhythmogenic (20-22). Holter monitoring during continuous glucose monitoring detected episodes of hypoglycaemia has documented runs of cardiac arrhythmias ranging from ventricular tachycardia (20) to bradycardia (21) and repolarization abnormalities have been identified in diabetes (22).

In the absence of large, long duration, prospective randomized trials it is not possible to establish causation definitively and severe hypoglycaemia clearly cannot be induced deliberately, in one arm, for both ethical and practical reasons. It has been argued that “confounding” may explain the association between mortality and hypoglycaemia, i.e., that a comorbidity (such as renal or liver disease, weight loss or cognitive impairment) confers both an increased risk of mortality and hypoglycaemia. Zoungas and colleagues (7) have speculated that confounding contributed to the association between mortality and severe hypoglycaemia in the ADVANCE trial. That was based on the association they observed between non-cardiovascular mortality (as well as cardiovascular mortality) and severe hypoglycaemia; they reasoned that death from respiratory, gastrointestinal or skin disorders was unlikely to be caused by hypoglycaemia. However, the conclusion that the associations between mortality and hypoglycaemia are causal is further supported by a systematic review, meta-analysis and bias analysis of studies involving 903,510 participants with T2DM, which concluded that comorbid severe illness alone may not explain these associations since comorbid illnesses would have had to be extremely strongly associated with both cardiovascular disease and severe hypoglycaemia (23).

Given that glycaemic goals in diabetes are a trade-off between glycaemic control and iatrogenic hypoglycaemia, it has been suggested that a reasonable individualized glycaemic goal is the lowest hemoglobin A1C that does not cause severe hypoglycaemia and preserves awareness of hypoglycaemia, preferably with little or no symptomatic or even asymptomatic hypoglycaemia at a given stage in the evolution of the individual’s diabetes (24). Parenthetically, the substantial relationship between a lower A1C level and a higher incidence of severe hypoglycaemia has been consistently documented in randomized controlled clinical trials in both T1DM (25,26) and T2DM (27-29). In these trials when patients with diabetes were randomly assigned to intensive glycaemic therapy and shown to have lower A1C levels or to more conventional glycaemic goals and shown to have higher A1C levels, the incidence of severe hypoglycaemia was 2- to 3-fold higher in each of the groups with the lower A1C levels. The frequency of hypoglycaemia was inversely related to the A1C level in both the original DCCT and the follow-up EDIC phase (25,26), although the slope was less steep in the EDIC phase. The extent to which the latter is the result of insulin analogues, improved insulin delivery, glucose monitoring, patient education, patient or caregiver skill or some other factor is not known.

In an extensive review, with the exception of a 15% reduction of non-fatal myocardial infarction, Rodriguez-Gutierrez and Montori (30) found no significant impact of tight glycaemic control of T2DM on outcomes important to patients—end stage renal disease/dialysis, renal death, blindness, clinical neuropathy, cardiovascular or all-cause mortality, stroke or amputation or peripheral vascular disease. They did find a 2- to 3-fold increase in severe hypoglycaemia during intensive therapy. The authors concluded that the overwhelming consensus in favour of tight glycaemic control to prevent complications needs to recalibrated. That tight glycaemic control did not reduce mortality in T2DM was also reported in an earlier meta-analysis (31). Some of these reservations could also be applied to T1DM. But, there is an association between mortality and substantial elevations in A1C levels in T1DM (32,33). In a 27-year follow-up of DCCT patients a rise in mortality above that of the general U. S. population began only with an A1C level greater than 9% (75 mmol/mol) (32). An analysis of a much larger data set, disclosed a similar finding (33). At 30 years of follow-up previous intensive glycaemic therapy (i.e., during the DCCT) did not reduce major cardiovascular events significantly, although the trend was in that direction (34). Given these data (32-34) one might conclude that the overwhelming consensus for intensive glycaemic therapy for the prevention of macrovascular complications (35), like that for microvascular complications (30), is stronger than the evidence to support it.

Clearly, we must carefully match therapeutic benefit and harm when we select a glycaemic goal in a patient with diabetes. Therapy with insulin is life-saving and prevents symptomatic hyperglycaemia in T1DM and many with advanced T2DM, but these benefits, like the prevention of macrovascular complications (32-34), do not require intensive glycaemic control. If we cannot convincingly document clinically important benefits of intensive glycaemic control we can advocate intensive glycaemic therapy only if the treatment is free from harm. But, many patients with diabetes are at risk for therapeutic harm.  For example, those with hypoglycaemia-associated autonomic failure (including both defective glucose counterregulation and impaired awareness of hypoglycaemia), a history of severe hypoglycaemia, a long duration of diabetes, chronic kidney disease or malnutrition are at risk for hypoglycaemia (1). Exclusion of such patients would eliminate many patients with insulin-treated diabetes, perhaps most with T1DM (1,2), from intensive glycaemic therapy. Furthermore, since potential cardiovascular benefits develop over decades (34) one cannot anticipate benefit in patients with chronic vascular complications or other comorbidities with a short life expectancy. In these groups a less stringent glycaemic goal is indicated (36), perhaps an A1C level less than 8.5% (69 mmol/mol) (37) rather than less than 7% (53 mmol/mol) (35). In short, it is difficult to justify attempts to maintain A1C levels less than 7% (53 mmol/mol) in patients at high risk of harm or with no likelihood of benefit. Diabetes could be considered over-treated in such patients. At the very least, the risks and benefits should be explained to patients and their family before embarking on such an approach.

About the Authors

 

Acknowledgements: This manuscript was prepared without external support or assistance. Dr. Cryer has served as a consultant to Novo Nordisk in recent years. Dr. Heller has undertaken consultancy and worked on advisory boards on behalf of Eli Lilly, Novo Nordisk, Takeda and Boeringher Ingelheim for which his institution has received fees and he has received personal fees from Novo Nordisk, Astra Zeneca, Roche for work on speaker panels.

Correspondence
Philip E. Cryer, MD
Division of Endocrinology, Metabolism and Lipid Research (Campus Box 8127)
Washington University School of Medicine
660 South Euclid Avenue
St. Louis, Missouri 63110 U. S. A.

Email:  pcryer@wustl.edu
Phone:  1-314-502-0075
Fax: 1-314-362-7616

Simon R. Heller, DM, FRCP
Department of Oncology and Metabolism
University of Sheffield School of Medicine
Beech Hill Road
Sheffield S10 1UK
UK

References

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