Defining hypoglycaemia: what level has clinical relevance?

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

Heine has discussed in detail the difficulties of accurate measurement by this method.

“and Heine has discussed in detail the difficulties of accurate measurement by this method [9].”

• cites [9] Heine RJ (1993) Methods of investigation of insulin-induced hypoglycaemia. In: Frier BM, Fisher BM (eds) Hypoglycaemia and diabetes: clinical and physiological aspects. Edward Arnold, London, pp 165–175Not checked yet

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Classified as probably not a substantial claim.

The ADA Workgroup argued that 3.9 mmol/l is the glycaemic level at which hormonal counter-regulation is activated in non-diabetic adults.

“The ADA Workgroup argued that this is the glycaemic level at which hormonal counter-regulation is activated in non-diabetic adults [4,5]”

• cites [4] Schwartz NS, Clutter WE, Shah SD, Cryer PE (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 79:777–781 sourceNot checked yet

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• cites [5] Mitrakou A, Ryan C, Veneman T et al (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol Endocrinol Metab 260:E67–E74 sourceNot checked yet

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May combine two claims.

Induction of hypoglycaemia using a glucose clamp technique is highly unphysiological and does not simulate how hypoglycaemia occurs in people treated with insulin.

“In addition, induction of hypoglycaemia using a glucose clamp technique is highly unphysiological and does not simulate how hypoglycaemia occurs in people treated with insulin”

• AssumptionRests on an assumption: The key studies on counter-regulation were performed using hyperinsulinaemic glucose clamp with plasma glucose measured from arterialised venous blood.

May combine two claims.

In the hypoglycaemic range, the arteriovenous difference is small (probably less than 0.2 mmol/l), but it can be influenced considerably by the level and duration of hyperinsulinaemia.

“In the hypoglycaemic range the arteriovenous difference is small (probably less than 0.2 mmol/l), but it can be influenced considerably by the level and duration of hyperinsulinaemia [8].”

• cites [7] Liu D, Moberg E, Kollind M, Lins P-E, Adamson U, Macdonald IA (1992) Arterial, arterialized venous, venous and capillary blood glucose measurements in normal man during hyperinsulinaemic euglycaemia and hypoglycaemia. Diabetologia 35:287–290 sourceNot checked yet

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• cites [8] Liu D, Moberg E, Kollind M, Lins P-E, Adamson U (1991) A high concentration of circulating insulin suppresses the glucagon response to hypoglycemia in normal man. J Clin Endocrinol Metab 73:1123–1128 sourceNot checked yet

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May combine two claims.

It is misleading to infer that the onset of counter-regulation is a sudden all-or-none phenomenon or that glycaemic thresholds for counter-regulatory secretion can be measured with precision.

“It is misleading to infer that the 'onset of counter-regulation' [2] is a sudden all-or-none phenomenon or that glycaemic thresholds for counter-regulatory secretion can be measured with precision.”

Classified as probably not a substantial claim.

The ADA Workgroup proposed that any blood glucose value at or below 3.9 mmol/l should represent hypoglycaemia, whether or not symptoms are present.

“The one contentious issue is their proposal that any blood glucose value equal to, or below, 3.9 mmol/l (70 mg/dl) should represent hypoglycaemia, whether or not symptoms are present.”

• cites [2] American Diabetes Association Workgroup on Hypoglycemia (2005) Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 28:1245–1249 sourceNot checked yet

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May combine two claims.

Vea et al. showed mean intraindividual differences of 0.22 mmol/l for secretion of counter-regulatory hormones and 0.25 mmol/l for onset of symptoms.

“The reproducibility of the glycaemic thresholds was studied in normal individuals by Vea et al. [10], who showed mean intraindividual differences of 0.22 mmol/l for the secretion of counter-regulatory hormones and 0.25 mmol/l for the onset of symptoms.”

• cites [10] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35:958–961 sourceNot checked yet

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Classified as probably not a substantial claim.

Swinnen et al. applied a range of different glucose levels defining hypoglycaemia to blood glucose data from two large prospective trials of people with type 2 diabetes who had commenced insulin.

“To illustrate this, Swinnen et al. [3] applied a range of different glucose levels defining hypoglycaemia to the blood glucose data from two large prospective trials of people with type 2 diabetes who had commenced treatment with insulin.”

• cites [3] Swinnen SGHA, Mullins P, Miller M, Hoekstra JBL, Holleman F (2009) Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia doi: 10.1007/s00125-008-1147-0 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Swinnen et al. suggest that exposure to blood glucose levels between 3.5 and 3.9 mmol/l is unlikely to be of great clinical consequence and argue that the ADA definition of 3.9 mmol/l is set too high to have clinical credibility.

“The authors suggest that exposure to blood glucose levels between 3.5 and 3.9 mmol/l is unlikely to be of great clinical consequence and argue that the ADA definition of 3.9 mmol/l is set at too high a level to have clinical credibility.”

• cites [3] Swinnen SGHA, Mullins P, Miller M, Hoekstra JBL, Holleman F (2009) Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia doi: 10.1007/s00125-008-1147-0 sourceNot checked yet

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May combine two claims.

The sensitivity to identify severe hypoglycaemia was not greatly enhanced by setting the definition at a higher blood glucose level, but the specificity was lowered considerably.

“The sensitivity to identify severe hypoglycaemia was not greatly enhanced by setting the definition of hypoglycaemia at a higher blood glucose level, but the specificity was lowered considerably.”

• cites [3] Swinnen SGHA, Mullins P, Miller M, Hoekstra JBL, Holleman F (2009) Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia doi: 10.1007/s00125-008-1147-0 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The ADA Workgroup argued that antecedent hypoglycaemia of this modest degree can reduce secretion of glucagon and adrenaline in response to subsequent hypoglycaemia.

“and that antecedent hypoglycaemia of this modest degree can reduce the secretion of the counterregulatory hormones glucagon and adrenaline (epinephrine) in response to a subsequent episode of hypoglycaemia [6].”

• cites [6] Davis SN, Shavers C, Mosqueda-Garcia R, Costa F (1997) Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46:1328–1335 sourceNot checked yet

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May combine two claims.

Glycaemic thresholds differ between non-diabetic individuals, and accurate determination of thresholds is difficult in all individuals, irrespective of insulin-treated diabetes.

“Not only do glycaemic thresholds differ between non-diabetic individuals, but accurate determination of the thresholds is difficult in all individuals, irrespective of whether or not they have insulin-treated diabetes.”

• cites [10] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35:958–961 sourceNot checked yet

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• cites [11] Frier BM (2007) Impaired awareness of hypoglycaemia. In: Frier BM, Fisher M (eds) Hypoglycaemia in clinical diabetes, 2nd edn. Wiley, Chichester, pp 141–170 sourceNot checked yet

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

Another glucose clamp study reported that a mere 5 min of antecedent hypoglycaemia (at arterialised venous blood glucose 2.9 mmol/l) influenced subsequent counter-regulatory responses to hypoglycaemia, but not symptoms.

“These results are in contrast to those from another glucose clamp study, which reported that a mere 5 min of antecedent hypoglycaemia (at an arterialised venous blood glucose level of 2.9 mmol/l) influenced subsequent counter-regulatory responses to hypoglycaemia, but not symptoms [16].”

• cites [16] Davis SN, Mann S, Galassetti P et al (2000) Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans. Diabetes 49:1897–1903 sourceNot checked yet

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May combine two claims.

The key study cited by the ADA Workgroup as providing evidence for a definitive effect of antecedent hypoglycaemia at a plasma glucose of 3.9 mmol/l involved observations in eight young non-diabetic adults, whose symptom responses were not measured.

“The key study cited by the ADA Workgroup as providing evidence for a definitive effect of antecedent hypoglycaemia at a plasma glucose of 3.9 mmol/l, again derived from arterialised venous blood, involved observations in eight young non-diabetic adults, whose symptom responses were not measured [6].”

• cites [6] Davis SN, Shavers C, Mosqueda-Garcia R, Costa F (1997) Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46:1328–1335 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

It is debatable whether modest secretion of counter-regulatory hormones at blood glucose levels between 3.5 and 4.0 mmol/l has pathological significance, and in normal health may simply represent a glucose homeostatic mechanism.

“It is debatable whether modest secretion of counter-regulatory hormones at blood glucose levels between 3.5 and 4.0 mmol/l has pathological significance, and in normal health may simply represent a glucose homeostatic mechanism that maintains glucose within a narrow physiological range.”

May combine two claims.

Most studies demonstrating these effects have subjected volunteers to antecedent hypoglycaemia using a glucose clamp for around 60 min, a duration which may occur during sleep but would be unusual during waking hours.

“However, most studies demonstrating these effects have subjected volunteers to antecedent hypoglycaemia using a glucose clamp for around 60 min, a duration which may certainly occur during sleep, but would be unusual during waking hours.”

May combine two claims.

3.5 mmol/l is still above the accepted glycaemic thresholds for the onset of manifestations of hypoglycaemia from sympathoadrenal stimulation and cognitive dysfunction, and activation of these responses generates autonomic and neuroglycopenic warning symptoms.

“It is still above the accepted glycaemic thresholds for the onset of the manifestations of hypoglycaemia that result from the stimulation of the sympathoadrenal system and the onset of cognitive dysfunction, and it is the activation of these responses that generate autonomic and neuroglycopenic warning symptoms.”

May combine two claims.

An effect on glucagon and epinephrine responses to subsequent hypoglycaemia was described, but the significance of these findings to diabetes is unknown and they have not yet been replicated.

“An effect on the glucagon and epinephrine responses to subsequent hypoglycaemia was described [6], but the significance of these findings to diabetes is unknown and they have not yet been replicated.”

• cites [6] Davis SN, Shavers C, Mosqueda-Garcia R, Costa F (1997) Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46:1328–1335 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

By defining biochemical hypoglycaemia as a capillary blood glucose level of 3.5 mmol/l or lower, the unnecessary inflation of the frequency of clinically meaningless biochemical hypoglycaemia in clinical studies could be avoided.

“By defining biochemical hypoglycaemia as a capillary blood glucose level of 3.5 mmol/l or lower, the unnecessary inflation of the frequency of clinically meaningless biochemical hypoglycaemia in clinical studies could be avoided.”

May combine two claims.

In non-diabetic volunteers and in people with type 1 diabetes who have normal awareness of hypoglycaemia and reasonable glycaemic control, symptomatic responses are not usually generated, and cognitive dysfunction does not commence, until the arterialised venous blood glucose level approaches 3.2 mmol/l.

“In non-diabetic volunteers and in people with type 1 diabetes who have normal awareness of hypoglycaemia and reasonable glycaemic control, symptomatic responses are not usually generated, and cognitive dysfunction does not commence, until the (arterialised venous) blood glucose level approaches 3.2 mmol/l [11].”

• cites [11] Frier BM (2007) Impaired awareness of hypoglycaemia. In: Frier BM, Fisher M (eds) Hypoglycaemia in clinical diabetes, 2nd edn. Wiley, Chichester, pp 141–170 sourceNot checked yet

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May combine two claims.

These glycaemic thresholds are dynamic in people with diabetes and can be influenced by factors such as quality of glycaemic control or development of impaired hypoglycaemia awareness.

“In addition, these glycaemic thresholds are dynamic in people with diabetes and can be influenced by many factors, such as the quality of glycaemic control or the development of impaired hypoglycaemia awareness [11].”

• cites [11] Frier BM (2007) Impaired awareness of hypoglycaemia. In: Frier BM, Fisher M (eds) Hypoglycaemia in clinical diabetes, 2nd edn. Wiley, Chichester, pp 141–170 sourceNot checked yet

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May combine two claims.

Although these responses may be preceded by some release of counter-regulatory hormones in non-diabetic individuals, the absence of glucagon secretion in insulin-deficient diabetes negates the clinical importance of defining hypoglycaemia on this basis.

“Although these responses may be preceded by some release of counter-regulatory hormones in non-diabetic individuals, the absence of glucagon secretion in insulin-deficient diabetes negates the clinical importance of defining hypoglycaemia on this basis.”

Classified as probably not a substantial claim.

Swinnen et al. have clearly illustrated how a small change in the cut-off level can magnify the prevalence of asymptomatic hypoglycaemia.

“While the difference between 3.5 and 3.9 mmol/l may appear to be insignificant, Swinnen et al. [3] have clearly illustrated how a small change in the cut-off level can magnify the prevalence of asymptomatic hypoglycaemia.”

• cites [3] Swinnen SGHA, Mullins P, Miller M, Hoekstra JBL, Holleman F (2009) Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia doi: 10.1007/s00125-008-1147-0 sourceNot checked yet

  Not checked in the free run.