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Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society

Open access
Seaquist, Elizabeth R., Anderson, John, Childs, Belinda, Cryer, Philip, Dagogo-Jack, Samuel, Fish, Lisa, Heller, Simon R., Rodriguez, Henry +2 more·2013·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2012-4127
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Abstract

OBJECTIVE: To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS: Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE: The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS: Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS: The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

AI snapshot

Written from the paper’s full text.

TL;DR

This consensus report from a joint American Diabetes Association/The Endocrine Society workgroup reviews evidence on iatrogenic hypoglycemia in diabetes and updates clinical guidance on its definition, its impact on outcomes, treatment targets, and prevention. It reaffirms the ≤70 mg/dL (≤3.9 mmol/L) alert value and the five-category classification of hypoglycemia, and identifies knowledge gaps for future research.

Key findings

  • The workgroup defines iatrogenic hypoglycemia as all episodes of abnormally low plasma glucose that expose the individual to potential harm, and recommends an alert value of ≤70 mg/dL (≤3.9 mmol/L) for patients treated with a sulfonylurea, glinide, or insulin; it retains the five-category classification (severe, documented symptomatic, asymptomatic, probable symptomatic, pseudo-hypoglycemia).
  • Severe hypoglycemia event rates range from 115 to 320 per 100 patient-years in type 1 diabetes and 35 to 70 per 100 patient-years in type 2 diabetes; because type 2 diabetes is more prevalent, most episodes including severe ones occur in type 2 diabetes.
  • Hypoglycemia-associated autonomic failure (HAAF) is associated with a 25-fold or greater increased risk of severe hypoglycemia during intensive glycemic therapy, and is at least partly reversible by scrupulous avoidance of hypoglycemia (symptom restoration within 2 weeks, complete reversal by 3 months in published studies).
  • In ACCORD, intensive-arm participants had threefold higher hypoglycemia and a 20% increase in mortality; those with one or more severe hypoglycemic episodes had higher death rates across both arms (hazard ratio 1.41 [95% CI 1.03–1.93]). In VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days.
  • Inpatient data: of 31,970 general-ward admissions, 3,349 (10.5%) had at least one episode of hypoglycemia (≤70 mg/dL); of 5,365 ICU admissions, 102 (1.9%) had at least one severe hypoglycemic episode (<40 mg/dL).

Methods

  • Design: consensus report/workgroup statement; five ADA and five Endocrine Society members with hypoglycemia expertise met via planning conference call and a 2-day meeting, with subsequent e-mail/phone communication and iterative document revision.
  • Evidence: the writing group considered data from recent clinical trials and other studies to update the prior 2005 workgroup report; unpublished data were not used, and expert opinion was used to develop some conclusions.
  • Consensus process: achieved by group discussion and iterative revisions; approved by ADA's Professional Practice Committee (October 2012) and Board Executive Committee (November 2012), and by The Endocrine Society's Clinical Affairs Core Committee (October 2012) and Council (November 2012).

Limitations

  • Stated: the report is a consensus statement in which expert opinion was used to develop some conclusions, and unpublished data were not used.
  • Stated: the true incidence and prevalence of hypoglycemia among hospitalized patients are not known precisely; in ACCORD, glycemia was not measured at the time of death, so the role of hypoglycemia in mortality may never be known.
  • Evident from the text: several key associations (e.g., hypoglycemia and subsequent mortality, hypoglycemia and dementia) derive from post hoc analyses in which causality cannot be established, and the authors note existing data on cognition are "somewhat contradictory."

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Integrity signals

Registry

Crossref · 10.1210/jc.2012-4127

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation
    § The challenge of measuring glucose accurately · p. 2

    In critical care units, POC meter performance may be compromised by medications (vasopressors, acetaminophen), treatments (oxygen), and clinical states (hypotension, anemia).

    “In critical care units, where the accuracy of POC meters is particularly crucial, their performance may be compromised by medications (vasopressors, acetaminophen), treatments (oxygen), and clinical states (hypotension, anemia) (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Klonoff, 2011, Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation
    § How should hypoglycemia in diabetes be de fi ned and reported? · p. 2

    The alert value approximates the glycemic thresholds for activation of glucose counterregulatory systems in nondiabetic individuals.

    “Given the limited accuracy of the monitoring devices, it approximates the lower limit of the normal postabsorptive plasma glucose concentration (15), the glycemic thresholds for activation of glucose counterregulatory systems in nondiabetic individuals (15), and the upper limit of plasma glucose level reported to reduce counterregulatory responses to subsequent hypoglycemia (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Cryer, 2001, The prevention and correction of hypoglycemia

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  • Premisecitation
    § The challenge of measuring glucose accurately · p. 2

    Karon et al. found that if there were a total measurement error of 20%, 1- and 2-step errors in insulin dose would occur 45% and 6% of the time, respectively, in a tight glycemic control protocol.

    “Karon et al. (18) translated these measurement errors into potential insulin-dosing errors using simulation modeling and found that if there were a total measurement error of 20%, 1- and 2-step errors in insulin dose would occur 45% and 6% of the time, respectively, in a tight glycemic control protocol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Karon, 2010, Glucose meter performance criteria for tight glycemic control estimated by simulation modeling, Clin Chem source

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  • Premisecitation
    § The challenge of measuring glucose accurately · p. 2

    Retrospective and real-time CGMs have poor accuracy in the hypoglycemic range as demonstrated by error grid analysis.

    “However, the accuracy of CGMs in the hypoglycemic range is poor as demonstrated by error grid analysis (19,20).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Clarke, 1987, Evaluating clinical accuracy of systems for self-monitoring of blood glucose, Diabetes Care source

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    • cites [20] Parkes, 2000, A new consensus error grid to evaluate the clinical significance of inaccuracies in the measurement of blood glucose, Diabetes Care source

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  • Premisecitation
    § How should hypoglycemia in diabetes be de fi ned and reported? · p. 2

    The alert value approximates the lower limit of the normal postabsorptive plasma glucose concentration.

    “Given the limited accuracy of the monitoring devices, it approximates the lower limit of the normal postabsorptive plasma glucose concentration (15), the glycemic thresholds for activation of glucose counterregulatory systems in nondiabetic individuals (15), and the upper limit of plasma glucose level reported to reduce counterregulatory responses to subsequent hypoglycemia (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Cryer, 2001, The prevention and correction of hypoglycemia

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  • May combine two claims. 25
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    Interpretationcitation
    § The challenge of measuring glucose accurately · p. 2

    Such imprecision may affect the safe implementation of insulin infusion protocols in critical care units and may account in part for the high hypoglycemia rates in most trials of inpatient intensive glycemic control.

    “Such imprecision may affect the safe implementation of insulin infusion protocols in critical care units and may account in part for the high hypoglycemia rates in most trials of inpatient intensive glycemic control.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § The challenge of measuring glucose accurately · p. 2

    Freckmann et al. found that only 15 of 27 meters on the market in Europe several years ago met the current analytical standards of ±15 mg/dL in the hypoglycemia range, 2 of 27 met ±10 mg/dL, and none were capable of measuring ±5 mg/dL.

    “Despite this relatively large permissible variation, Freckmann et al. (16) found that only 15 of 27 meters on the market in Europe several years ago met the current analytical standards of 6 15 mg/dL in the hypoglycemia range, 2 of 27 met 6 10 mg/dL, and none were capable of measuring 6 5 mg/dL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Freckmann, 2010, System accuracy evaluation of 27 blood glucose monitoring systems according to DIN EN ISO 15197, Diabetes Technol Ther source

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    Interpretationcitation
    § How should hypoglycemia in diabetes be de fi ned and reported? · p. 2

    Because the alert value is higher than the glycemic threshold for symptoms in nondiabetic individuals and those with well-controlled diabetes, it generally allows time to prevent a clinical hypoglycemic episode and provides some margin for the limited accuracy of monitoring devices at low-glucose levels.

    “Because it is higher than the glycemic threshold for symptoms in both nondiabetic individuals and those with wellcontrolled diabetes (9,13,14), it generally allows time to prevent a clinical hypoglycemic episode and provides some margin for the limited accuracy of monitoring devices at low-glucose levels.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Amiel, 1988, Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release, Diabetes source

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    • cites [13] Boyle, 1988, Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics, N Engl J Med source

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    • cites [14] Cryer, 2009, Preventing hypoglycaemia: what is the appropriate glucose alert value?, Diabetologia source

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    Interpretationreasoning
    § The challenge of measuring glucose accurately · p. 2

    The need for accurate meters in the <75 mg/dL range is essential in insulin-treated patients, whether outpatients or inpatients, but less important in outpatients on medications that rarely cause hypoglycemia.

    “The need for accurate meters in the , 75 mg/dL range is essential in insulintreated patients, whether they are outpatients or inpatients, but it is less important in those outpatients who are on medications that rarely cause hypoglycemia.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § How should hypoglycemia in diabetes be de fi ned and reported? · p. 2

    The alert value of ≤70 mg/dL is data driven and pragmatic.

    “This alert value is data driven and pragmatic (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Cryer, 2009, Preventing hypoglycaemia: what is the appropriate glucose alert value?, Diabetologia source

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    Premisecitation
    § Impact of hypoglycemia on patients with type 2 diabetes · p. 4

    In the ACCORD trial, subjects randomly assigned to the intensive arm experienced a 20% increase in mortality, and the glycemic control study was stopped early due to this finding.

    “In the ACCORD trial, subjects who were randomly assigned to the intensive arm also experienced a 20% increase in mortality, and the glycemic control study was stopped early due to this fi nding.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Gerstein, 2008, Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med source

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    Interpretationcitation
    § Hypoglycemia unawareness and hypoglycemia-associated autonomic failure · p. 3

    HAAF is maladaptive because defective glucose counterregulation and hypoglycemia unawareness substantially increase the risk of severe hypoglycemia with its morbidity and potential mortality.

    “On the other hand, HAAF is clearly maladaptive since defective glucose counterregulation and hypoglycemia unawareness substantially increase the risk of severe hypoglycemia with its morbidity and potential mortality (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Cryer, 2011, Death during intensive glycemic therapy of diabetes: mechanisms and implications, Am J Med source

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    Interpretationcitation
    § Scientific Statement · p. 3

    Although profound and prolonged hypoglycemia can cause brain death, most episodes of fatal hypoglycemia are probably the result of other mechanisms, such as ventricular arrhythmias.

    “Although profound and prolonged hypoglycemia can cause brain death, most episodes of fatal hypoglycemia are probably the result of other mechanisms, such as ventricular arrhythmias (26).”
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    • cites [26] Cryer, 2011, Death during intensive glycemic therapy of diabetes: mechanisms and implications, Am J Med source

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    Premisecitation
    § The challenge of measuring glucose accurately · p. 2

    The accuracy of CGMs, like POC meters, is negatively affected by multiple factors in hospitalized patients, and they are calibrated with POC meters affected by those same factors.

    “Because the accuracy of CGMs, like POC meters, is negatively affected by multiple factors in hospitalized patients and they are calibrated with POC meters affected by those same factors, CGMs are not recommended for glycemic management in hospitalized patients at this time (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Klonoff, 2011, Continuous glucose monitoring: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

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    Premisecitation
    § Impact of hypoglycemia on patients with type 2 diabetes · p. 4

    A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.

    “A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Duckworth, 2009, Glucose control and vascular complications in veterans with type 2 diabetes, N Engl J Med source

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    • cites [4] Gerstein, 2008, Effects of intensive glucose lowering in type 2 diabetes, N Engl J Med source

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    • cites [5] Patel, 2008, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N Engl J Med source

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    Premisecitation
    § Hypoglycemia unawareness and hypoglycemia-associated autonomic failure · p. 3

    HAAF is a form of functional sympathoadrenal failure that is most often caused by recent antecedent iatrogenic hypoglycemia and is at least partly reversible by scrupulous avoidance of hypoglycemia.

    “HAAF is a form of functional sympathoadrenal failure that is most often caused by recent antecedent iatrogenic hypoglycemia (25) and is at least partly reversible by scrupulous avoidance of hypoglycemia (32 -34).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [25] Cryer, 2008, The barrier of hypoglycemia in diabetes, Diabetes source

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    • cites [32] Cranston, 1994, Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes, Lancet source

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    • cites [33] Dagogo-Jack, 1994, Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM, Diabetes source

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    • cites [34] Fanelli, 1994, Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM, Diabetologia source

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    Interpretationreasoning
    § Impact of hypoglycemia on patients with type 2 diabetes · p. 4

    Potential lethal mechanisms that might be provoked by hypoglycemia could cause mortality downstream of the hypoglycemic event, increasing the difficulty in establishing cause and effect.

    “However, the potential lethal mechanisms that might be provoked by hypoglycemia could cause mortality downstream of the hypoglycemic event, increasing the dif fi culty in establishing cause and effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Impact of hypoglycemia on hospitalized patients · p. 5

    Persons with diabetes are three times more likely to be hospitalized than those without diabetes.

    “Persons with diabetes are three times more likely to be hospitalized than those without diabetes, and approximately 25% of hospitalized patients (including people without a history of diabetes) have hyperglycemia (62 -65).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [62] American Diabetes Association, 2008, Economic costs of diabetes in the U.S. in 2007, Diabetes Care source

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    • cites [63] Aubert, 1995

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    • cites [64] Clement, 2004, Management of diabetes and hyperglycemia in hospitals, Diabetes Care source

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    • cites [65] Umpierrez, 2002, Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes, J Clin Endocrinol Metab source

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    Premisecitation
    § Impact of hypoglycemia on the elderly · p. 4

    Epidemiological studies show that hypoglycemia is the most frequent metabolic complication experienced by older adults in the U.S.

    “Epidemiological studies show that hypoglycemia is the most frequent metabolic complication experienced by older adults in the U.S. (50).”
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    • cites [50] Bertoni, 2002, Diabetes-related morbidity and mortality in a national sample of U.S. elders, Diabetes Care source

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    Premisecitation
    § Impact of hypoglycemia on hospitalized patients · p. 5

    Approximately 25% of hospitalized patients, including people without a history of diabetes, have hyperglycemia.

    “Persons with diabetes are three times more likely to be hospitalized than those without diabetes, and approximately 25% of hospitalized patients (including people without a history of diabetes) have hyperglycemia (62 -65).”
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    • cites [62] American Diabetes Association, 2008, Economic costs of diabetes in the U.S. in 2007, Diabetes Care source

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    • cites [63] Aubert, 1995

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    • cites [64] Clement, 2004, Management of diabetes and hyperglycemia in hospitals, Diabetes Care source

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    • cites [65] Umpierrez, 2002, Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes, J Clin Endocrinol Metab source

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    Premisecitation
    § Impact of hypoglycemia on patients with type 2 diabetes · p. 4

    One-third of all deaths in ACCORD were due to cardiovascular disease, and hypoglycemia was associated with higher cardiovascular mortality.

    “One-third of all deaths were due to cardiovascular disease, and hypoglycemia was associated with higher cardiovascular mortality.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Bonds, 2010, The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study, BMJ source

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    Premisecitation
    § Impact of hypoglycemia on hospitalized patients · p. 5

    Inpatient hyperglycemia has been associated with prolonged hospital length of stay and with numerous adverse outcomes including mortality.

    “Inpatient hyperglycemia has been associated with prolonged hospital length of stay and with numerous adverse outcomes including mortality (64,66 -68).”
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    • cites [64] Clement, 2004, Management of diabetes and hyperglycemia in hospitals, Diabetes Care source

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    • cites [66] Bucerius, 2003, Impact of diabetes mellitus on cardiac surgery outcome, Thorac Cardiovasc Surg source

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    • cites [67] Capes, 2001, Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview, Stroke source

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    • cites [68] McCowen, 2001, Stress-induced hyperglycemia, Crit Care Clin source

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    Premisecitation
    § Impact of hypoglycemia on patients with type 2 diabetes · p. 4

    In the opinion of the blinded adjudication committee assigned to investigate mortality in ACCORD, hypoglycemia was judged to have a definite role in one death, a probable role in three deaths, and a possible role in 38 deaths, which represents a role in less than 10% of the deaths recorded in the study population while the glycemic intervention was active.

    “In the opinion of the blinded adjudication committee assigned to investigate mortality in ACCORD, hypoglycemia was judged to have a de fi nite role in only one death, a probable role in three deaths, and a possible role in 38 deaths (46), which represents a role in less than 10% of the deaths recorded in the study population while the glycemic intervention was active.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Bonds, 2010, The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study, BMJ source

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    Premisecitation
    § Impact of hypoglycemia during pregnancy · p. 5

    For women with type 1 diabetes, severe hypoglycemia occurs 3-5 times more frequently in the first trimester and at a lower rate in the third trimester when compared with the incidence in the year preceding the pregnancy.

    “For women with type 1 diabetes, severe hypoglycemia occurs 3 -5 times more frequently in the fi rst trimester and at a lower rate in the third trimester when compared with the incidence in the year preceding the pregnancy (80).”
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    • cites [80] Ringholm, 2012, Hypoglycaemia during pregnancy in women with Type 1 diabetes, Diabet Med source

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    Premisecitation
    § Exercise management · p. 7

    Risk factors for exertional hypoglycemia include prolonged exercise duration, unaccustomed exercise intensity, and inadequate energy supply in relation to ambient insulinemia.

    “The risk factors for exertional hypoglycemia include prolonged exercise duration, unaccustomed exercise intensity, and inadequate energy supply in relation to ambient insulinemia (113,114).”
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    • cites [113] Chipkin, 2001, Exercise and diabetes, Cardiol Clin source

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    • cites [114] Zinman, 2003, Physical activity/exercise and diabetes mellitus, Diabetes Care source

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    Premisecitation
    § Impact of hypoglycemia on hospitalized patients · p. 5

    In a retrospective analysis of 4,368 admissions involving 2,582 diabetic patients admitted to the general ward, severe hypoglycemia ≤50 mg/dL was associated with increased length of stay and greater odds of inpatient death and death within 1 year of hospital discharge.

    “With regard to impact, a retrospective analysis of 4,368 admissions involving 2,582 diabetic patients admitted to the general ward indicated that severe hypoglycemia ( # 50 mg/dL) was associated with increased length of stay and greater odds of inpatient death and death within 1 year of hospital discharge (77).”
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    • cites [77] Turchin, 2009, Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward, Diabetes Care source

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    Premisecitation
    § Medication adjustment · p. 7

    In published studies, avoiding frequent hypoglycemia required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values.

    “In published studies, this has required frequent (almost daily) contact between clinician and patient, and adjustments to caloric intake and insulin regimen based on blood glucose values (10,119,120).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Dagogo-Jack, 1993, Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia, J Clin Invest source

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    • cites [119] Amiel, 1987, Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus, N Engl J Med source

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    • cites [120] Fanelli, 1993, Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM, Diabetes source

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    Premisecitation
    § Seaquist and Associates · p. 6

    These programs have been successfully delivered in other settings with comparable reductions in hypoglycemic risk.

    “These programs have been successfully delivered in other settings (103,104) with comparable reductions in hypoglycemic risk (105).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [103] DAFNE Study Group, 2002, Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial, BMJ source

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    • cites [104] McIntyre, 2010, Dose adjustment for normal eating (DAFNE)—an audit of outcomes in Australia, Med J Aust source

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    • cites [105] Hopkins, 2012, 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 source

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    Premisecitation
    § Seaquist and Associates · p. 6

    The Insulin Treatment and Training programs developed by Mühlhauser and Berger have reported improved glycemic control comparable with DCCT while reducing the rates of severe hypoglycemia.

    “The Insulin Treatment and Training programs developed by M € uhlhauser and Berger (100) have reported improved glycemic control comparable with DCCT while reducing the rates of severe hypoglycemia (101,102).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Mühlhauser, 2002, Patient education—evaluation of a complex intervention, Diabetologia source

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    • cites [101] Bott, 1997, Intensified insulin therapy and the risk of severe hypoglycaemia, Diabetologia source

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    • cites [102] Sämann, 2005, Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study, Diabetologia source

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    Premisecitation
    § Impact of hypoglycemia on hospitalized patients · p. 5

    Risk factors for inpatient hypoglycemia include older age, presence of comorbidities, diabetes, increasing number of antidiabetic agents, tight glycemic control, septic shock, renal insufficiency, mechanical ventilation, and severity of illness.

    “The risk factors for inpatient hypoglycemia include older age, presence of comorbidities, diabetes, increasing number of antidiabetic agents, tight glycemic control, septic shock, renal insuf fi ciency, mechanical ventilation, and severity of illness (75,76).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Boucai, 2011, Hypoglycemia-associated mortality is not drug-associated but linked to comorbidities, Am J Med source

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    • cites [76] Krinsley, 2007, Severe hypoglycemia in critically ill patients: risk factors and outcomes, Crit Care Med source

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    Premisecitation
    § Impact of hypoglycemia on quality of life and activities of daily living · p. 5

    Patients with recurrent hypoglycemia have been found to have chronic mood disorders including depression and anxiety, although it is hard to establish cause and effect between hypoglycemia and mood changes.

    “Patients with recurrent hypoglycemia have been found to have chronic mood disorders including depression and anxiety (85,86), although it is hard to establish cause and effect between hypoglycemia and mood changes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Gold, 1997, Hypoglycaemia and non-cognitive aspects of psychological function in insulin-dependent (type 1) diabetes mellitus (IDDM), Diabet Med source

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    • cites [86] Strachan, 2000, Recovery of cognitive function and mood after severe hypoglycemia in adults with insulin-treated diabetes, Diabetes Care source

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    Premisecitation
    § Medication adjustment · p. 7

    With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.

    “With this approach, restoration of autonomic symptoms of hypoglycemia occurred within 2 weeks, and complete reversal of hypoglycemia unawareness was achieved by 3 months.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Dagogo-Jack, 1993, Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia, J Clin Invest source

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    • cites [119] Amiel, 1987, Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus, N Engl J Med source

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    • cites [120] Fanelli, 1993, Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Impact of hypoglycemia during pregnancy · p. 5

    When pregnant and nonpregnant women are compared with CGM, mild hypoglycemia (blood glucose <60 mg/dL) is more common in all pregnant women, but equally so regardless of whether or not they have diabetes, either pregestational or gestational.

    “When pregnant and nonpregnant women are compared with CGM, mild hypoglycemia (de fi ned by the authors as blood glucose , 60 mg/dL) is more common in all pregnant women, but equally so regardless of whether or not they have diabetes, either pregestational or gestational (81).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Mazze, 2012, Measuring glucose exposure and variability using continuous glucose monitoring in normal and abnormal glucose metabolism in pregnancy, J Matern Fetal Neonatal Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Medication adjustment · p. 7

    The return of hypoglycemic symptom awareness was associated with a modest increase (approximately 0.5%) in HbA1c values, but others have reported no loss of glycemic control.

    “The return of hypoglycemic symptom awareness was associated with a modest increase ( ; 0.5%) in HbAlc values (33), but others have reported no loss of glycemic control (32,34).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Dagogo-Jack, 1994, Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM, Diabetes source

      Not checked in the free run.

    • cites [32] Cranston, 1994, Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes, Lancet source

      Not checked in the free run.

    • cites [34] Fanelli, 1994, Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Glucose monitoring · p. 8

    With low-glucose alarms set at 108 mg/dL, 4 weeks of real-time CGM use restored the epinephrine response and improved adrenergic symptoms during a hyperinsulinemic hypoglycemic clamp in a small group of adolescents with type 1 diabetes and hypoglycemic unawareness.

    “With the low-glucose alarms set at 108 mg/dL, 4 weeks of real-time CGM use restored the epinephrine response and improved adrenergic symptoms during a hyperinsulinemic hypoglycemic clamp in a small group of adolescents with type 1 diabetes and hypoglycemic unawareness (122).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Ly, 2011, Improving epinephrine responses in hypoglycemia unawareness with real-time continuous glucose monitoring in adolescents with type 1 diabetes, Diabetes Care source

      Not checked in the free run.

30 of 30

  • The paper relies on this without support.

    Hypoglycemia is a common problem in children with type 1 diabetes because of challenges presented by insulin dosing, variable eating patterns, erratic activity, and the limited ability of small children to detect hypoglycemia.

    “Hypoglycemia is a common problem in children with type 1 diabetes because of the challenges presented by insulin dosing, variable eating patterns, erratic activity, and the limited ability of small children to detect hypoglycemia.”

  • The paper relies on this without support.

    Infants and toddlers may not recognize the symptoms of hypoglycemia and lack the ability to effectively communicate their distress.

    “Infants and toddlers may not recognize the symptoms of hypoglycemia and lack the ability to effectively communicate their distress.”

  • The paper relies on this without support.

    Puberty is associated with insulin resistance, while normal developmental stages of adolescence may lead to inattention to diabetes and increased risk for hypoglycemia.

    “Puberty is associated with insulin resistance, while at the same time the normal developmental stages of adolescence may lead to inattention to diabetes and increased risk for hypoglycemia.”

  • The paper relies on this without support.

    The youngest patients are most vulnerable to the adverse consequences of hypoglycemia.

    “The youngest patients are most vulnerable to the adverse consequences of hypoglycemia.”

  • The paper relies on this without support.

    Age-related declines in renal function and hepatic enzyme activity may interfere with the metabolism of sulfonylureas and insulin, thereby potentiating their hypoglycemic effects.

    “Age-related declines in renal function and hepatic enzyme activity may interfere with the metabolism of sulfonylureas and insulin, thereby potentiating their hypoglycemic effects.”

  • The paper relies on this without support.

    Although severe hypoglycemia is common in older individuals with both type 1 and type 2 diabetes, patients with type 2 diabetes tend to have longer hospital stays and greater medical costs.

    “Although severe hypoglycemia is common in older individuals with both type 1 and type 2 diabetes, patients with type 2 diabetes tend to have longer hospital stays and greater medical costs.”

  • The paper relies on this without support.

    Impaired sympathoadrenal activation is generally confined to the response to hypoglycemia, and autonomic activities in organs such as the heart, gastrointestinal tract, and bladder appear to be unaffected.

    “Impaired sympathoadrenal activation is generally con fi ned to the response to hypoglycemia, and autonomic activities in organs such as the heart, gastrointestinal tract, and bladder appear to be unaffected.”

  • The paper relies on this without support.

    Risk factors for severe hypoglycemia in pregnancy include a history of severe hypoglycemia in the preceding year, impaired hypoglycemia awareness, long duration of diabetes, low HbA1c in early pregnancy, fluctuating plasma glucose levels, and excessive use of supplementary insulin between meals.

    “Risk factors for severe hypoglycemia in pregnancy include a history of severe hypoglycemia in the preceding year, impaired hypoglycemia awareness, long duration of diabetes, low HbA1c in early pregnancy, fl uctuating plasma glucose levels, and excessive use of supplementary insulin between meals.”

  • The paper relies on this without support.

    Hypoglycemia is generally without risk for the fetus as long as the mother avoids injury during the episode.

    “Hypoglycemia is generally without risk for the fetus as long as the mother avoids injury during the episode.”

  • The paper relies on this without support.

    For women with preexisting diabetes, insulin requirements rise throughout pregnancy and then drop precipitously at delivery of the placenta, requiring an abrupt reduction in insulin dosing to avoid postdelivery hypoglycemia.

    “For women with preexisting diabetes, insulin requirements rise throughout the pregnancy and then drop precipitously at the time of delivery of the placenta, requiring an abrupt reduction in insulin dosing to avoid postdelivery hypoglycemia.”

  • The paper relies on this without support.

    Early in the course of type 2 diabetes, most patients are treated with lifestyle changes and metformin, neither of which causes hypoglycemia.

    “Early in the course of the disease, most patients are treated with lifestyle changes and metformin, neither of which causes hypoglycemia.”

  • The paper relies on this without support.

    Recurrent hypoglycemia increases the risk of severe hypoglycemia and the development of hypoglycemia unawareness and HAAF.

    “Recurrent hypoglycemia increases the risk of severe hypoglycemia and the development of hypoglycemia unawareness and HAAF.”

  • The paper relies on this without support.

    Dissociated meal and insulin injection patterns lead to wide fluctuations in plasma glucose levels.

    “Dissociated meal and insulin injection patterns lead to wide fl uctuations in plasma glucose levels.”

  • The paper relies on this without support.

    Physical activity increases glucose utilization, which increases the risk of hypoglycemia.

    “Physical activity increases glucose utilization, which increases the risk of hypoglycemia.”

  • The paper relies on this without support.

    Patients who develop hypoglycemia unawareness do so because of frequent and recurrent hypoglycemia.

    “Patients who develop hypoglycemia unawareness do so because of frequent and recurrent hypoglycemia.”

  • The paper relies on this without support.

    Older adults with diabetes have a disproportionately high number of clinical complications and comorbidities, all of which can be exacerbated by and sometimes contribute to episodes of hypoglycemia.

    “Older adults with diabetes have a disproportionately high number of clinical complications and comorbidities, all of which can be exacerbated by and sometimes contribute to episodes of hypoglycemia.”

  • The paper relies on this without support.

    Hypoglycemia continues to cause considerable morbidity and even mortality in patients with diabetes.

    “However, hypoglycemia continues to cause considerable morbidity and even mortality in patients with diabetes.”
17 of 17

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recurrent hypoglycaemia is associated with mood disorders.

    “In addition, observational research has found that recurrent hypoglycaemia (low blood sugar) is associated with mood disorders.9”

    From Food and mood: How do diet and nutrition affect mental wellbeing? (2020) · cites this paper as [9]

  • High dietary glycaemic load, and the resultant compensatory responses, could lower plasma glucose to concentrations that trigger the secretion of autonomic counter-regulatory hormones such as cortisol, adrenaline, growth hormone, and glucagon.

    “Thus, high dietary glycaemic load, and the resultant compensatory responses, could lower plasma glucose to concentrations that trigger the secretion of autonomic counter-regulatory hormones such as cortisol, adrenaline, growth hormone, and glucagon.5 9”

    From Food and mood: How do diet and nutrition affect mental wellbeing? (2020) · cites this paper as [9]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. Cryer, 2001, The prevention and correction of hypoglycemia, 1057
  2. Reno, 2011, Deaths due to severe hypoglycemia are exacerbated by diabetes and ameliorated by hypoglycemic pre-conditioning (Abstract), Diabetes, 60, A81
  3. Aubert, 1995, Diabetes-Related Hospitalization and Hospital Utilization

Cited by

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Related

Authors
Seaquist, E. R., Anderson, J., Childs, B., Cryer, P., Dagogo-Jack, S., Fish, L., Heller, S. R., Rodriguez, H., Rosenzweig, J., & Vigersky, R.
Affiliations
  • University of Minnesota (US)
  • Tennessee Department of Transportation (US)
  • Mid-America Diabetes Associates (B.C.), Wichita, Kansas
  • Washington University in St. Louis (US)
  • University of Tennessee Health Science Center (US)
  • Park Nicollet Clinic (US)
  • University of Sheffield (GB)
  • University of South Florida (US)
  • Boston University (US)
  • Walter Reed National Military Medical Center (US)
Corresponding author
Seaquist, Elizabeth R.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2013-05-01
Volume
98
Issue
5
Pages
1845-1859
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2012-4127
OpenAlex
W2031264880
Cited by
412
References
127
Citations by year
2026: 13 · 2025: 16 · 2024: 25 · 2023: 42 · 2022: 42 · 2021: 41 · 2020: 55 · 2019: 40 · 2018: 37 · 2017: 30 · 2016: 27 · 2015: 23 · 2014: 17 · 2013: 4
FWCI
18.60
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
  • American Diabetes Association
  • Eli Lilly and Company
  • Sanofi
  • National Institute for Health and Care Research (NF-SI-0611-10248)
  • Novo Nordisk
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Health Professions › Emergency Medical Services › Patient Safety and Medication Errors
Keywords
hypoglycemia, diabetes mellitus, hypoglycemia definition, hypoglycemia prevention, long-term outcomes, patient counseling, clinical guidelines
MeSH terms
Activities of Daily Living, Aging, Blood Glucose, Combined Modality Therapy, Diabetes Mellitus, Diet, Diabetic, Female, Humans, Hypoglycemia, Hypoglycemic Agents, Male, Patient Education as Topic, Pregnancy, Pregnancy in Diabetics, Quality of Life, Exercise, Diabetes, Gestational, Drug Monitoring, Evidence-Based Medicine

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