Hypoglycemia in Type 2 Diabetes

May combine two claims.

In an observational study in our own center of 41 people with type 2 diabetes treated with bedtime NPH insulin and oral antidiabetic drugs, 49% had experienced infrequent mild hypoglycemia since commencing insulin, with an incidence of four episodes per patient per year and no episodes of severe hypoglycemia.

“In an observational study in our own center of 41 people with type 2 diabetes treated with bedtime NPH (isophane) insulin and oral antidiabetic drugs, 49% had experienced infrequent mild hypoglycemia since commencing insulin, with an incidence of four episodes per patient per year and no episodes of severe hypoglycemia (130).”

• cites [130] Allen KV, McAulay V, Sommerfield AJ, Frier BM: Hypoglycaemia is uncommon with a combination of antidiabetic drugs and bedtime NPH insulin for type 2 diabetes. Pract Diab Int 21: 179–182,2004 sourceNot checked yet

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In humans, the initial response to a decline in blood glucose is suppression of endogenous insulin secretion followed by release of counterregulatory hormones, of which glucagon and epinephrine are the most potent.

“In humans, the initial response to a decline in blood glucose is suppression of endogenous insulin secretion followed by release of counterregulatory hormones, of which glucagon and epinephrine (adrenaline) are the most potent.”

• cites (3)(4)(5)(6)Not checked yet

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Classified as probably not a substantial claim.

Hypoglycemia has been considered a minor problem of the treatment modalities used for type 2 diabetes.

“but has been considered to be a minor problem of the treatment modalities used for type 2 diabetes (2)”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

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Early studies comparing counterregulatory hormonal responses in young and older nondiabetic adults yielded conflicting results, and many participants had comorbidities that confounded interpretation of the data.

“Early studies (17-21) that compared these responses in young and older nondiabetic adults yielded conflicting results, and many of the participants had comorbidities that confounded interpretation of the data.”

• cites [17] Hochstaedt BB, Shneebaum M, Shadel M: Adrenocortical responsivity in old age. Gerontologia Clinica 3: 239–246,1961 sourceNot checked yet

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• cites [18] Friedman M, Greeb M, Shraland DE: Assessment of hypothalamo-pituitary-adrenal function in the geriatric age group. J Gerontol 24: 292–297,1969 sourceNot checked yet

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• cites [19] Kalk WJ, Virik AI, Pimstone BL, Jackson WPU: Growth hormone response to insulin hypoglycemia in the elderly. J Gerontol 28: 431–433,1973 sourceNot checked yet

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• cites [20] Muggeo M, Fedele D, Tiengo A, Molinari M, Crepaldi G: Human GH and cortisol response to insulin stimulation in the aged. J Gerontol 30: 546–551,1975 sourceNot checked yet

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• cites [21] Schramm VA, Pusch HJ, Franke H, Haubitz I: Hormonal adaptive capacity in old age: behaviour of hormonal parameters after insulin hypoglycaemia in young and old patients. Fortschr Med 99: 1255–1260,1981Not checked yet

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May combine two claims.

The juxtaposition of these thresholds may limit the time available to self-treat and increase the risk of developing incapacitating neuroglycopenia.

“The juxtaposition of these thresholds may limit the time available to self-treat and increase the risk of developing incapacitating neuroglycopenia.”

May combine two claims.

When blood glucose falls in a nondiabetic adult, the secretion of counterregulatory hormones and the onset of cognitive, physiological, and symptomatic changes occur at reproducible blood glucose thresholds within a defined hierarchy.

“When blood glucose falls in a nondiabetic adult, the secretion of counterregulatory hormones and the onset of cognitive, physiological, and symptomatic changes occur at reproducible blood glucose thresholds (4,7) within a defined hierarchy (5)”

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

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• cites [7] Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Di Vincenzo A, Modarelli F, Ciofetta M, Lepore M, Annibale B, Torlone E, Periello G, De Feo P, Santeusanio F, Brunetti P, Bolli GB: Long term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia following institution of rational intensive therapy in IDDM. Diabetologia 37: 1265–1276,1994 sourceNot checked yet

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• cites [5] Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am J Physiol 266: E67–E74,1991 sourceNot checked yet

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In a small British study, symptom scores were significantly lower in older nondiabetic adults than in younger people; autonomic and neuroglycopenic symptoms were affected equally.

“In a small British study (12) that compared responses to hypoglycemia in seven (five male) nondiabetic adults, aged 65-80 years, with six (three male) younger people, aged 24 -49 years, the symptom scores were significantly lower in the older group; autonomic and neuroglycopenic symptoms were affected equally.”

• cites [12] Brierley EJ, Broughton DL, James OFW, Alberti KGMM: Reduced awareness of hypoglycaemia in the elderly despite an intact counterregulatory response. Q J Med 88: 439–445,1995Not checked yet

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Symptomatic responses to hypoglycemia were similar in elderly people with and without type 2 diabetes, suggesting that decreased symptom intensity is associated with increasing age independent of diabetes.

“A further study (16) by the same group reported that symptomatic responses were similar in 10 elderly people with (7 male, aged 72 Ϯ 1 years) and 10 without (6 male, aged 74 Ϯ 1 years) type 2 diabetes, suggesting that the decreased symptom intensity observed in their first study was associated with increasing age, independent of any effects of diabetes.”

• cites [16] Meneilly GS, Cheung E, Tuokko H: Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 43: 403–410,1994 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

With increasing use of insulin to treat type 2 diabetes, the actual prevalence of hypoglycemia is likely to escalate.

“with the increasing use of insulin to treat type 2 diabetes, the actual prevalence of hypoglycemia is likely to escalate.”

May combine two claims.

Hypoglycemia was induced mostly with an intravenous bolus injection of insulin, producing variable degrees of hypoglycemia, and principally examined cortisol and growth hormone responses, so these results are of limited value.

“Hypoglycemia was induced mostly with an intravenous bolus injection of insulin, producing variable degrees of hypoglycemia, and principally examined cortisol and growth hormone responses (17)(18)(19)(20)(21), so these results are of limited value.”

• cites (17)(18)(19)(20)(21)Not checked yet

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

Hypoglycemia is a major limitation in achieving good control in type 1 diabetes.

“Hypoglycemia is recognized to be a major limitation in achieving good control in type 1 diabetes (1)”

• cites [1] Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45: 937–948,2002 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The burden of covert hypoglycemia associated with oral antidiabetic agents may be underestimated.

“The burden of covert hypoglycemia associated with oral antidiabetic agents may be underestimated”

May combine two claims.

Hypoglycemic symptoms are idiosyncratic and age specific.

“Hypoglycemic symptoms are idiosyncratic and age specific (10).”

• cites [10] McAulay V, Deary IJ, Frier BM: Symptoms of hypoglycaemia in people with diabetes. Diabet Med 18: 690–705,2001 sourceNot checked yet

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With increasing age, the symptoms of hypoglycemia may become less intense and the symptom profile is modified.

“With increasing age, the symptoms of hypoglycemia may become less intense (12,13) and the symptom profile is modified (9,12,14).”

• cites [12] Brierley EJ, Broughton DL, James OFW, Alberti KGMM: Reduced awareness of hypoglycaemia in the elderly despite an intact counterregulatory response. Q J Med 88: 439–445,1995Not checked yet

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• cites [13] Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA: Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care 20: 135–141,1997 sourceNot checked yet

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• cites [9] Deary IJ: Symptoms of hypoglycaemia and effects on mental performance and emotions. In Hypoglycaemia in Clinical Diabetes. Frier BM, Fisher BM, Eds. Chichester, U.K., John Wiley and Sons,1999, p. 29–54Not checked yet

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• cites [14] Jaap AJ, Jones GC, McCrimmon RJ, Deary IJ, Frier BM: Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin. Diabet Med 15: 398–401,1998 sourceNot checked yet

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May combine two claims.

In young adults, symptomatic responses to hypoglycemia are generated at a blood glucose level higher than the level at which cognitive function becomes impaired, allowing sufficient time to take corrective action before severe neuroglycopenia supervenes.

“In young adults, symptomatic responses to hypoglycemia are generated at a blood glucose level that is higher than the level at which cognitive function becomes impaired.This allows sufficient time to take corrective action before severe neuroglycopenia supervenes (5).”

• cites [5] Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J: Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms and cerebral dysfunction. Am J Physiol 266: E67–E74,1991 sourceNot checked yet

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May combine two claims.

Few investigations of hypoglycemia in type 2 diabetes have taken age into account when designing studies and analyzing results, and few studies have included patients aged >70 years.

“Few investigations of hypoglycemia in type 2 diabetes have taken age into account when designing studies and analyzing results, and few studies have included patients aged Ͼ70 years (Tables 1 and 2).”

May combine two claims.

Although various counterregulatory hormonal deficiencies have been described in type 2 diabetes, these were mostly mild, and epinephrine secretion was invariably preserved.

“Although various counterregulatory hormonal deficiencies have been described in type 2 diabetes, these were mostly mild, and epinephrine secretion was invariably preserved.”

May combine two claims.

Type 2 diabetes may therefore confer greater protection against hypoglycemia, particularly when glycemic control is suboptimal, because the counterregulatory responses commence at higher blood glucose levels than observed in the nondiabetic state or in people with type 1 diabetes.

“Type 2 diabetes may therefore confer greater protection against hypoglycemia, particularly when glycemic control is suboptimal, because the counterregulatory responses commence at higher blood glucose levels than observed in the nondiabetic state or in people with type 1 diabetes (37,38).”

• cites [37] Korzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, Amiel S: Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care 21: 283–290,1998 sourceNot checked yet

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• cites [38] Levy CJ, Kinsley BT, Bajaj M, Simonson DC: Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM. Diabetes Care 21: 1330–1338,1998 sourceNot checked yet

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In both nondiabetic and type 1 diabetic subjects, female subjects have lower counterregulatory responses to hypoglycemia than male subjects, although no information is available in type 2 diabetes.

“In both nondiabetic and type 1 diabetic subjects, female subjects have lower counterregulatory responses to hypoglycemia than male subjects (39 -42), although no information is available in type 2 diabetes.”

• cites [39] Amiel SA, Maran A, Powrie JK, Umpleby AM, Macdonald IA: Gender differences in counterregulation to hypoglycaemia. Diabetologia 36: 460–464,1993 sourceNot checked yet

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• cites [40] Davis SN, Fowler S, Costa F: Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes 49: 56–72,2000 sourceNot checked yet

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• cites [41] Davis SN, Shavers C, Costa F: Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds. Am J Physiol 279: E1054–E1063,2000 sourceNot checked yet

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• cites [42] Sandoval DA, Ertl AC, Richardson MA, Tate DB, Davis SN: Estrogen blunts neuroendocrine and metabolic responses to hypoglycemia. Diabetes 52: 1749–1755,2003 sourceNot checked yet

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Most investigators reporting preservation of the glucagon response have studied people with type 2 diabetes who were unlikely to be insulin deficient, and, with one exception, all of these studies have examined counterregulatory responses in middle-aged subjects in their 5th or 6th decade.

“Most investigators reporting preservation of the glucagon response have studied people with type 2 diabetes who were unlikely to be insulin deficient (33,34,36,38), and, with one exception (16), all of these studies have examined counterregulatory responses in middle-aged subjects in their 5th or 6th decade.”

• cites [33] Heller SR, Macdonald IA, Tattersall RB: Counterregulation in type II (non-insulin-dependent) diabetes mellitus: normal endocrine and glycaemic responses up to 10 years after diagnosis. Diabetologia 30: 924–929,1987 sourceNot checked yet

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• cites [34] Boden G, Soriano M, Hoeldtke RD, Owen OE: Counterregulatory hormone release and glucose recovery after hypoglycemia in non-insulin-dependent patients. Diabetes 32: 231–237,1983 sourceNot checked yet

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• cites [36] Spyer G, Hattersley A, Macdonald IA, Amiel S, MacLeod KM: Hypoglycemic counterregulation at normal blood glucose concentrations in patients with well controlled type 2 diabetes. Lancet 356: 1970–1974,2000 sourceNot checked yet

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• cites [38] Levy CJ, Kinsley BT, Bajaj M, Simonson DC: Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM. Diabetes Care 21: 1330–1338,1998 sourceNot checked yet

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• cites [16] Meneilly GS, Cheung E, Tuokko H: Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 43: 403–410,1994 sourceNot checked yet

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May combine two claims.

The glucagon response to hypoglycemia was intact in tablet-treated patients and nondiabetic control subjects but was almost absent in insulin-deficient patients, demonstrating acquired counterregulatory abnormalities in association with insulin deficiency.

“The glucagon response to hypoglycemia was intact in the tablettreated patients and in the nondiabetic control subjects but was almost absent in the insulin-deficient patients (Fig. 4), demonstrating the presence of acquired counterregulatory abnormalities in association with insulin deficiency.”

• cites [51] Segel SA, Paramore DA, Cryer PE: Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 51: 724–733,2002 sourceNot checked yet

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The rate of insulin clearance from the circulation declines with age, which may enhance the risk of hypoglycemia in elderly people.

“The rate of insulin clearance from the circulation declines with age (24 -26), which may enhance the risk of hypoglycemia in elderly people.”

• cites [24] Reaven GM, Greenfield MS, Mondon CE, Rosenthal M, Wright D, Reaven EP: Does insulin removal rate from plasma decline with age?Diabetes 31: 670–673,1982 sourceNot checked yet

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• cites [25] Minaker KL, Rowe JW, Torino R, Pallotta JA: Influence of age on clearance of insulin in man. Diabetes 31: 851–855,1982 sourceNot checked yet

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• cites [26] Fink RI, Revers RR, Kolterman OG, Olefsky JM: The metabolic clearance of insulin and the feedback inhibition of insulin secretion are altered with ageing. Diabetes 34: 275–280,1985 sourceNot checked yet

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In type 1 diabetes, deficiency of the secretory response of glucagon to hypoglycemia is an early acquired abnormality of counterregulation; the catecholamine response compensates for several years but declines with time.

“In type 1 diabetes, deficiency of the secretory response of glucagon to hypoglycemia is an early acquired abnormality of counterregulation.The catecholamine response compensates for several years but declines with time (1).”

• cites [1] Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45: 937–948,2002 sourceNot checked yet

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Evidence exists in nondiabetic and type 1 diabetic subjects to implicate hyperinsulinemia per se in suppressing the release of glucagon in response to hypoglycemia while increasing catecholamine and cortisol release, although this has been disputed.

“Evidence exists in nondiabetic and type 1 diabetic subjects to implicate hyperinsulinemia per se in suppressing the release of glucagon in response to hypoglycemia (43-46) while increasing catecholamine and cortisol release (47), although this has been disputed (48).”

• cites [43] Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Ciofetta M, Modarelli F, Di Vincenzo A, Annibale B, Lepore M, Lalli C, Del Sindaco P, Brunetti P, Bolli GB: Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia 37: 797–807,1994 sourceNot checked yet

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• cites [44] Diamond MP, Hallerman L, Starick-Zych K, Jones TW, Connolly-Howard M, Tamborlane WV, Sherwin RS: Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 72: 1388–1390,1991 sourceNot checked yet

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• cites [45] Liu D, Moberg E, Kollind M, Lins PE, Adamson U: A high concentration of circulating insulin suppresses the glucagon response to hypoglycemia in normal man. J Clin Endocrinol Metab 73: 1123–1128,1991 sourceNot checked yet

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• cites [46] Liu DT, Adamson UC, Lins PE, Kollind ME, Moberg EA, Andreasson K: Inhibitory effect of circulating insulin on glucagon secretion during hypoglycemia in type I diabetic patients. Diabetes Care 15: 59–65,1991 sourceNot checked yet

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• cites [47] Davis SN, Goldstein RE, Jacobs J, Price L, Wolfe R, Cherrington AD: The effects of differing insulin levels on the hormonal and metabolic response to equivalent hypoglycemia in normal humans. Diabetes 42: 263–272,1993 sourceNot checked yet

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• cites [48] Davis SN, Goldstein RE, Price L, Jacobs J, Cherrington AD: The effects of insulin on the counterregulatory response to equivalent hypoglycemia in patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 77: 1300–1307,1993 sourceNot checked yet

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Interpretation of early studies is limited by heterogeneity of study design, differences in blood glucose nadir between the diabetic and control groups, a lack of age-matched control subjects, and the disparate methods used to induce hypoglycemia.

“Interpretation of the early studies is limited by heterogeneity of study design (29), differences in blood glucose nadir between the diabetic and control groups (30,31), a lack of agematched control subjects (31), and the disparate methods used to induce hypoglycemia (30 -35).”

• cites [29] De Galan BE, Hoekstra JBL: Glucose counterregulation in type 2 diabetes mellitus. Diabet Med 18: 519–527,2001 sourceNot checked yet

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• cites [30] Bolli G, Tsalikian E, Haymond M, Cryer P, Gerich JE: Defective glucose counterregulation after subcutaneous insulin in noninsulin dependent diabetes mellitus: paradoxical lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses and islet paracrine interactions. J Clin Invest 73: 1532–1541,1984 sourceNot checked yet

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• cites [31] Campbell LV, Kraegen EW, Meler H, Lazarus L: Hormonal responses to insulin infusion in diabetes mellitus. Diabetologia 16: 359–364,1979 sourceNot checked yet

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May combine two claims.

Improving glycemic control with insulin therapy shifts the threshold for the counterregulatory response to a lower blood glucose level; a similar phenomenon is observed in type 1 diabetes when glycemic control is intensified.

“However, improving glycemic control with insulin therapy shifts the threshold for the counterregulatory response to a lower blood glucose level (37,38) (Fig. 3); a similar phenome-non is observed in type 1 diabetes when glycemic control is intensified (1,8,49).”

• cites [37] Korzon-Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, Amiel S: Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes. Diabetes Care 21: 283–290,1998 sourceNot checked yet

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• cites [38] Levy CJ, Kinsley BT, Bajaj M, Simonson DC: Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM. Diabetes Care 21: 1330–1338,1998 sourceNot checked yet

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• cites [1] Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45: 937–948,2002 sourceNot checked yet

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• cites [8] Frier BM, Fisher BM: Impaired hypoglycaemia awareness. In Hypoglycaemia in Clinical Diabetes. Frier BM, Fisher BM, Eds. Chichester, U.K., John Wiley and Sons,1999, p. 111–146Not checked yet

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• cites [49] Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes. Diabetes Care 26: 1902–1912,2003 sourceNot checked yet

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

In type 1 diabetes, mild hypoglycemia occurs on average around twice weekly.

“The frequency of hypoglycemia has been examined most extensively in people with type 1 diabetes, in whom mild hypoglycemia occurs on average around twice weekly (64,65).”

• cites [64] Pramming S, Thorsteinsson B, Bendtson I, Binder C: Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabet Med 8: 217–222,1991 sourceNot checked yet

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• cites [65] Pedersen-Bjergaard U, Pramming S, Heller SR Wallace TM, Rasmussen AK, Jorgensen HV, Matthews DR, Hougaard P, Thorsteinsson B: Severe hypoglycemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 20: 479–486,2004 sourceNot checked yet

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The DCCT participants were atypical, selected because they had a low risk of severe hypoglycemia, and the observed incidence of severe hypoglycemia was lower, ranging from 0.19 to 0.62 episodes per patient per year.

“They differ from the atypical participants of the Diabetes Control and Complications Trial (68), who had been selected because they had a low risk of severe hypoglycemia (71) and in whom the observed incidence of severe hypoglycemia was lower, ranging from 0.19 to 0.62 episodes per patient per year.”

• cites [68] 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. N Engl J Med 329: 977–986,1993 sourceNot checked yet

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• cites [71] Frier BM: Intensive glycaemic management in type 1 diabetes. In The Evidence Base for Diabetes Care. Williams R, Herman W, Kinmonth AL, Wareham NJ, Eds., Chichester, U.K., John Wiley and Sons,2002, p. 317–332 sourceNot checked yet

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With intensive treatment, hypoglycemia occurred most frequently in the insulin-treated patients, and the prevalence of hypoglycemia was lower in the 1st decade of the study than in later years.

“With intensive treatment, hypoglycemia occurred most frequently in the insulintreated patients, and the prevalence of hypoglycemia was lower in the 1st decade of the study than in later years (2) (Fig. 5).”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

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Antecedent hypoglycemia can modify the glycemic thresholds for responses to hypoglycemia in type 2 diabetes and may promote HAAF.

“Thus, antecedent hypoglycemia can modify the glycemic thresholds for responses to hypoglycemia in type 2 diabetes and may promote HAAF (53).”

• cites [51] Segel SA, Paramore DA, Cryer PE: Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 51: 724–733,2002 sourceNot checked yet

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• cites [53] Cryer PE: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350: 2272–2279,2004 sourceNot checked yet

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

In studies in northern Europe of unselected populations with type 1 diabetes, the estimated incidence of severe hypoglycemia ranges from 1.0 to 1.7 episodes per patient per year.

“In studies in northern Europe of unselected populations with type 1 diabetes, the estimated incidence of severe hypoglycemia ranges from 1.0 to 1.7 episodes per patient per year (65)(66)(67).”

• cites (65)(66)(67)Not checked yet

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The prevalence of hypoglycemia was lower when the groups were analyzed on an intention-to-treat basis because an increasing number of patients in the conventional treatment groups required the addition of treatment with sulfonylureas or insulin as their glycemic control deteriorated.

“The prevalence of hypoglycemia was lower when the groups were analyzed on an “intention-to-treat” basis because an increasing number of patients in the conventional treatment groups required the addition of treatment with sulfonylureas or insulin as their glycemic control deteriorated.”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

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Most people with type 2 diabetes are middle aged or elderly; accurate measures of the frequency of hypoglycemia are probably underestimated in the latter.

“Most people with type 2 diabetes are middle aged or elderly; accurate measures of the frequency of hypoglycemia are probably underestimated in the latter (57).”

• cites [57] McAulay V, Frier BM: Hypoglycaemia. In Diabetes in Old Age. 2nd ed. Sinclair AJ, Finucane P, Eds. Chichester, U.K., John Wiley and Sons,2001, p. 133–152 sourceNot checked yet

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In elderly people of either sex who have diabetes, unsteadiness and weakness are commonly reported symptoms of hypoglycemia, and a group of neurological symptoms affecting vision and coordination have been identified in addition to autonomic and neuroglycopenic symptoms.

“In elderly people of either sex who have diabetes, unsteadiness and weakness are commonly reported symptoms of hypoglycemia (60), and a group of neurological symptoms affecting vision and coordination have been identified in addition to autonomic and neuroglycopenic symptoms (10,14).”

• cites [60] Thomson FJ, Masson EA, Leeming JT, Boulton AJM: Lack of knowledge of symptoms of hypoglycaemia by elderly diabetic patients. Age Ageing 20: 404–406,1991 sourceNot checked yet

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• cites [10] McAulay V, Deary IJ, Frier BM: Symptoms of hypoglycaemia in people with diabetes. Diabet Med 18: 690–705,2001 sourceNot checked yet

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• cites [14] Jaap AJ, Jones GC, McCrimmon RJ, Deary IJ, Frier BM: Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin. Diabet Med 15: 398–401,1998 sourceNot checked yet

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May combine two claims.

The morbidity associated with hypoglycemia, such as impaired consciousness and convulsions, can be particularly debilitating in the elderly, who are at increased risk of injury and bone fractures because of general frailty and the presence of comorbidities, such as osteoporosis.

“The morbidity associated with hypoglycemia, such as impaired consciousness and convulsions, can be particularly debilitating in the elderly, who are at increased risk of injury and bone fractures because of general frailty and the presence of comorbidities, such as osteoporosis (57).”

• cites [57] McAulay V, Frier BM: Hypoglycaemia. In Diabetes in Old Age. 2nd ed. Sinclair AJ, Finucane P, Eds. Chichester, U.K., John Wiley and Sons,2001, p. 133–152 sourceNot checked yet

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In people with type 1 diabetes, recall of severe hypoglycemia is relatively robust over a period of 1 year, but recall of mild hypoglycemia is unreliable after an interval of 1 week.

“In people with type 1 diabetes, recall of severe hypoglycemia is relatively robust over a period of 1 year, but recall of mild hypoglycemia is unreliable after an interval of 1 week (64,72).”

• cites [64] Pramming S, Thorsteinsson B, Bendtson I, Binder C: Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabet Med 8: 217–222,1991 sourceNot checked yet

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• cites [72] Pedersen-Bjergaard U, Pramming S, Thorsteinsson B: Recall of severe hypoglycemia and self-estimated state of awareness in type 1 diabetes. Diabetes Metab Res Rev 19: 232–240,2003 sourceNot checked yet

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May combine two claims.

In a 7-year review of 102 cases of hypoglycemic coma secondary to either insulin or glyburide, 92 patients had type 2 diabetes, 7 sustained physical injury, 5 died, 2 suffered myocardial ischemia, and 1 patient had a stroke as a consequence of severe hypoglycemia.

“In a 7-year review of 102 cases of hypoglycemic coma secondary to either insulin or glyburide (glibenclamide), 92 patients had type 2 diabetes, 7 sustained physical injury, 5 died, 2 suffered myocardial ischemia, and 1 patient had a stroke as a consequence of severe hypoglycemia (59).”

• cites [59] Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y: Drug-induced hypoglycemic coma in 102 diabetic patients. Arch Intern Med 159: 281–284,1999 sourceNot checked yet

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

HAAF is a condition described in type 1 diabetes whereby recurrent hypoglycemia provokes failure of the centrally mediated sympatho-adrenal response, causing counterregulatory deficiency and impaired awareness of hypoglycemia.

“A condition labeled HAAF (hypoglycemia-associated autonomic failure) has been described in type 1 diabetes (52,53), whereby recurrent hypoglycemia provokes failure of the centrally mediated sympatho-adrenal response so causing counterregulatory deficiency and impaired awareness of hypoglycemia.”

• cites [52] Cryer PE: Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious cycle. Diabetes 41: 255–260,1992 sourceNot checked yet

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• cites [53] Cryer PE: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350: 2272–2279,2004 sourceNot checked yet

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Many elderly people with type 2 diabetes possess little knowledge of the symptoms and treatment of hypoglycemia, and this lack of knowledge extends to their relatives and caregivers.

“Many elderly people with type 2 diabetes possess little knowledge of the symptoms and treat-ment of hypoglycemia (60,61).This lack of knowledge extends to their relatives and caregivers (62).”

• cites [60] Thomson FJ, Masson EA, Leeming JT, Boulton AJM: Lack of knowledge of symptoms of hypoglycaemia by elderly diabetic patients. Age Ageing 20: 404–406,1991 sourceNot checked yet

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• cites [61] Pegg A, Fitzgerald D, Wise D, Singh BM, Wise PH: A community-based study of diabetes-related skills and knowledge in elderly people with insulin-requiring diabetes. Diabet Med 8: 778–781,1991 sourceNot checked yet

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• cites [62] Mutch WJ, Dingwall-Fordyce I: Is it a hypo? Knowledge of the symptoms of hypoglycaemia in elderly diabetic patients. Diabet Med 2: 54–56,1985 sourceNot checked yet

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

The annual prevalence of severe hypoglycemia in unselected type 1 diabetes populations is between 30% and 40%.

“The annual prevalence is between 30% (66,68,69) and 40% (67).”

• cites [66] MacLeod KM, Hepburn DA, Frier BM: Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabet Med 10: 238–245,1993 sourceNot checked yet

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• cites [68] 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. N Engl J Med 329: 977–986,1993 sourceNot checked yet

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• cites [69] Stephenson J, Fuller JH, the EURODIAB IDDM Complications Study Group: Microvascular and acute complications in IDDM patients: the EURODIAB IDDM complications study. Diabetologia 37: 278–285,1994 sourceNot checked yet

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• cites [67] ter Braak EWMT, Appelman AMMF, van de Laak M, Stolk RP, van Haeften TW, Erkelens DW: Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia. Diabetes Care 23: 1467–1471,2000 sourceNot checked yet

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Epinephrine stimulates release of glucose from the kidney, and in people who have a deficient glucagon response to hypoglycemia, this may compensate for their impaired hepatic glucose output.

“Epinephrine also stimulates release of glucose from the kidney, and, in people who have a deficient glucagon response to hypoglycemia, this may compensate for their impaired hepatic glucose output (55).”

• cites [55] Woerle HJ, Meyer C, Popa EM, Cryer PE, Gerich JE: Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal reciprocity. Diabetes 52: 1386–1392,2003 sourceNot checked yet

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In people with insulin-treated type 2 diabetes, recall of severe hypoglycemia also appears to be preserved over a period of 1 year, but reliability of their recall of mild hypoglycemia is unknown.

“In people with insulin-treated type 2 diabetes, recall of severe hypoglycemia also appears to be preserved over a period of 1 year (73), but reliability of their recall of mild hypoglycemia is unknown.”

• cites [73] Akram K, Pedersen-Bjergaard U, Borch-Johnsen K, Thorsteinsson B: Recall of severe hypoglycaemic episodes and course of hypoglycaemia awareness in insulin treated type 2 diabetes in one year follow-up (Abstract). Diabetologia 46 (Suppl. 2): A304,2003Not checked yet

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Plasma free fatty acids increase in response to hypoglycemia in type 2 diabetes but do not in type 1 diabetes.

“Plasma free fatty acids increase in response to hypoglycemia in type 2 diabetes (30,33,50) but do not in type 1 diabetes (54).”

• cites [30] Bolli G, Tsalikian E, Haymond M, Cryer P, Gerich JE: Defective glucose counterregulation after subcutaneous insulin in noninsulin dependent diabetes mellitus: paradoxical lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses and islet paracrine interactions. J Clin Invest 73: 1532–1541,1984 sourceNot checked yet

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• cites [33] Heller SR, Macdonald IA, Tattersall RB: Counterregulation in type II (non-insulin-dependent) diabetes mellitus: normal endocrine and glycaemic responses up to 10 years after diagnosis. Diabetologia 30: 924–929,1987 sourceNot checked yet

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• cites [50] Shamoon H, Friedman A, Canton C, Zacharowicz L, Hu M, Rossetti L: Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus. J Clin Invest 93: 2562–2571,1994 sourceNot checked yet

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• cites [54] Maggs DG, Jacob R, Rife F, Caprio S, Tamborlane WV, Sherwin RS: Counterregulation in peripheral tissues: effect of systemic hypoglycemia on levels of substrates and catecholamines in human skeletal muscle and adipose tissue. Diabetes 46: 70–76,1997 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Definitions of hypoglycemia differ between studies, hindering comparison, and most studies have reported retrospective data.

“Definitions of hypoglycemia differ between studies, hindering comparison, and most studies have reported retrospective data.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

It is difficult to derive equivalent figures for people with type 2 diabetes because of the heterogeneity of this disorder.

“It is difficult to derive equivalent figures for people with type 2 diabetes because of the heterogeneity of this disorder.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There is no evidence to suggest that in type 2 diabetes the principal causes of hypoglycemia (too much insulin or insulin secretagogue, physical exertion or inadequate carbohydrate consumption) differ from type 1 diabetes.

“There is no evidence to suggest that in type 2 diabetes the principal causes of hypoglycemia (too much insulin or insulin secretagogue, physical exertion or inadequate carbohydrate consumption) differ from type 1 diabetes.”

May combine two claims.

The UKPDS and VA CSDM trials, while frequently cited, are not representative of current treatment regimens and do not demonstrate the true frequency and risk of hypoglycemia.

“Thus, the U.K. Prospective Diabetes Study and Veterans Affairs Cooperative Study in Type 2 Diabetes trials, while frequently cited, are not representative of current treatment regimens and do not demonstrate the true frequency and risk of hypoglycemia.”

May combine two claims.

Although plasma C-peptide levels were not measured, it is likely that most of these subjects with insulin-treated type 2 diabetes were insulin deficient and were therefore at greater risk of hypoglycemia than people treated with oral antidiabetic agents.

“Although plasma Cpeptide levels were not measured, it is likely that most of these subjects with insulin-treated type 2 diabetes were insulin deficient and were therefore at greater risk of hypoglycemia than people treated with oral antidiabetic agents.”

• cites [81] Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP, the DARTS/MEMO Collaboration: Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population based study. Diabet Med 22: 449–455,2005 sourceNot checked yet

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In that survey, in type 1 diabetes, only 1 in 10 of those experiencing severe hypoglycemia required emergency service treatment compared with 1 in 3 of the group with type 2 diabetes.

“In the group with type 1 diabetes, only 1 in 10 of those experiencing severe hypoglycemia required emergency service treatment compared with 1 in 3 of the group with type 2 diabetes (81).”

• cites [81] Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP, the DARTS/MEMO Collaboration: Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population based study. Diabet Med 22: 449–455,2005 sourceNot checked yet

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In type 1 diabetes, severe hypoglycemia is often treated at home, and less than one-third of episodes are thought to need the assistance of the emergency medical services.

“In type 1 diabetes, severe hypoglycemia is often treated at home, and less than one-third of episodes are thought to need the assistance of the emergency medical services (80).”

• cites [80] Frier BM: Hypoglycaemia in the diabetic adult. Baillieres Clin Endocrinol Metab 7: 567–623,1993 sourceNot checked yet

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In an Australian study of 25 patients with type 2 diabetes treated with sulfonylureas, continuous monitoring recorded readings <2.2 mmol/l for at least 15 min in 56% of subjects and none were perceived.

“Readings of Ͻ2.2 mmol/l (Ͻ40 mg/dl) for at least 15 min were recorded in 56% of subjects and none were perceived (85).”

• cites [85] Hay LC, Wilmhurst EG, Fulcher G: Unrecognized hypo- and hyperglycemia in well-controlled patients with type 2 diabetes mellitus: the results of continuous glucose monitoring. Diab Technol Therap 5: 19–26,2003 sourceNot checked yet

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In the Diabetes Outcomes in Veterans Study, the probability of all hypoglycemia was greater in those who had a low mean blood glucose with a high SD, suggesting that the variability of blood glucose values is as important as A1C values in predicting the risk of hypoglycemia in insulin-treated type 2 diabetes.

“The probability of all hypoglycemia was greater in those who had a low mean blood glucose with a high SD, suggesting that the variability of blood glucose values is as important as A1C values in predicting the risk of hypoglycemia in insulintreated type 2 diabetes.”

• cites [86] Murata GH, Hoffman RM, Shah JH, Wendel CS, Duckworth WC: A probabilistic model for predicting hypoglycemia in type 2 diabetes mellitus. Arch Intern Med 164: 1445–1450,2004 sourceNot checked yet

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In a population survey in a region of Scotland, severe hypoglycemia required emergency treatment in 7.1% of patients with type 1 diabetes, in 7.3% of patients with insulin-treated type 2 diabetes, and in 0.8% of patients taking oral antidiabetic agents.

“Severe hypoglycemia had re-quired emergency treatment in 7.1% of patients with type 1 diabetes, in 7.3% of patients with insulin-treated type 2 diabetes, and in 0.8% of patients taking oral antidiabetic agents.”

• cites [79] Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, Frier BM, Morris AD, the DARTS/MEMO Collaboration: Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care 26: 1176–1180,2003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In that survey, severe hypoglycemia occurred in 0.5% of patients, all of whom had been treated with insulin.

“Severe hypoglycemia occurred in 0.5% of patients, all of whom had been treated with insulin.”

• cites [76] Miller CD, Philips LS, Ziemer DC, Gallina DL, Cook CB, El-Kebbi IM: Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 161: 1653–1659,2001 sourceNot checked yet

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May combine two claims.

In a prospective survey in the same region, the prevalence of all hypoglycemia (mild and severe) in the group with insulin-treated type 2 diabetes was 45% with an incidence of 16.4 episodes per patient per year.

“The prevalence of all hypoglycemia (mild and severe) in the group with insulin-treated type 2 diabetes was 45% with an incidence of 16.4 episodes per patient per year”

• cites [81] Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP, the DARTS/MEMO Collaboration: Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population based study. Diabet Med 22: 449–455,2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Compared with the nondiabetic state, people with type 2 diabetes have a normal rate of exercise-related skeletal muscle glucose uptake but an impaired hepatic glucose output, which can result in hypoglycemia during physical exertion.

“Compared with the nondiabetic state, people with type 2 diabetes have a normal rate of exercise-related skeletal muscle glucose uptake but an impaired hepatic glucose output (87), which can result in hypoglycemia during physical exertion.”

• cites [87] Chipkin SR, Klugh SA, Chasan-Taber L: Exercise and diabetes. Cardiol Clin 19: 489–505,2001 sourceNot checked yet

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The frequency of mild hypoglycemia was significantly higher in the intensively treated group (stepped vs. standard: 16.5 vs. 1.5 episodes per patient per year), but in the standard treatment group blood glucose was monitored less frequently so mild hypoglycemia may have been underreported.

“The frequency of mild hypoglycemia was significantly higher in the intensively treated group (stepped vs. standard: 16.5 vs. 1.5 episodes per patient per year), but in the standard treatment group blood glucose was monitored less frequently so mild hypoglycemia may have been underreported (74).”

• cites [74] Abraira C, Colwell JA, Nuttall FQ, Sawin CT, Nagel NJ, Comstock JP, Emanuele NV, Levin SR, Henderson W, Lee HS: Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial. Diabetes Care 18: 1113–1123,1995 sourceNot checked yet

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Exercise in type 2 diabetes results in improved insulin sensitivity and reduced postprandial plasma glucose levels.

“Exercise in type 2 diabetes results in improved insulin sensitivity (88) and reduced postprandial plasma glucose levels (89,90).”

• cites [88] Trovati M, Carta Q, Cavalot F, Vitali S, Banaudi C, Lucchina PG, Fiocchi F, Emanuelli G, Lenti G: Influence of physical training on blood glucose control, glucose tolerance, insulin secretion and insulin action in non-insulin-dependent diabetic patients. Diabetes Care 7: 416–420,1984 sourceNot checked yet

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• cites [89] Larsen JJ, Dela F, Kjaer M, Galbo H: The effect of moderate exercise on postprandial glucose homeostasis in NIDDM patients. Diabetologia 40: 447–453,1997 sourceNot checked yet

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• cites [90] Minuk HL, Vranic M, Marliss EB, Hanna AK, Albisser AM, Zinman B: Glucoregulatory and metabolic response to exercise in obese noninsulin-dependent diabetes. Am J Physiol 240: E458–E464,1981 sourceNot checked yet

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In a retrospective survey of 215 individuals with insulin-treated type 2 diabetes, only 8% had impaired awareness estimated by a validated scoring system, but those so affected had a ninefold greater incidence of hypoglycemia than those with intact awareness.

“One retrospective survey of 215 individuals with insulin-treated type 2 diabetes showed that only 8% had impaired awareness estimated by a validated scoring system (70), but those so affected had a ninefold greater incidence of hypoglycemia than those with intact awareness (82).”

• cites [70] Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care 17: 697–703,1994 sourceNot checked yet

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• cites [82] Henderson JN, Allen KV, Deary IJ, Frier BM: Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med 20: 1016–1021,2003 sourceNot checked yet

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In a retrospective Scottish survey in Edinburgh of 215 people with insulin-treated type 2 diabetes, the frequency of hypoglycemia increased with duration of insulin therapy and of diabetes and was inversely proportional to HbA1c concentration.

“A retrospective Scottish survey in Edinburgh of 215 people with insulintreated type 2 diabetes observed that the frequency of hypoglycemia increased with duration of insulin therapy and of diabetes and was inversely proportional to HbA 1c (A1C) concentration (82).”

• cites [82] Henderson JN, Allen KV, Deary IJ, Frier BM: Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med 20: 1016–1021,2003 sourceNot checked yet

  Not checked in the free run.

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In the VA CSDM, the overall incidence of severe hypoglycemia was 0.02 episodes per patient per year, and no significant difference was observed between the standard and stepped treatment groups.

“The overall incidence of severe hypoglycemia was 0.02 episodes per patient per year, and no significant difference was observed between the standard and stepped treatment groups.”

• cites [74] Abraira C, Colwell JA, Nuttall FQ, Sawin CT, Nagel NJ, Comstock JP, Emanuele NV, Levin SR, Henderson W, Lee HS: Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial. Diabetes Care 18: 1113–1123,1995 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Although patients were questioned about the occurrence of hypoglycemia at every 4-monthly review, only the most severe episode was documented, so underestimating the overall frequency.

“Although patients were questioned about the occurrence of hypoglycemia at every 4-monthly review, only the most severe episode was documented, so underestimating the overall frequency.”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

  Not checked in the free run.

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In that survey, the annual prevalence of severe hypoglycemia was 15% with an overall incidence of 0.28 episodes per patient per year.

“The annual prevalence of severe hypoglycemia was 15% with an overall incidence of 0.28 episodes per patient per year.”

• cites [82] Henderson JN, Allen KV, Deary IJ, Frier BM: Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med 20: 1016–1021,2003 sourceNot checked yet

  Not checked in the free run.

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Impaired awareness of hypoglycemia is a major risk factor for severe hypoglycemia in type 1 diabetes but is less common in people with type 2 diabetes.

“Impaired awareness of hypoglycemia is a major risk factor for severe hypoglycemia in type 1 diabetes (70) but is less common in people with type 2 diabetes (83).”

• cites [70] Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care 17: 697–703,1994 sourceNot checked yet

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• cites [83] Hepburn DA, MacLeod KM, Pell ACH, Scougal IJ, Frier BM: Frequency and symptoms of hypoglycaemia experienced by patients with type 2 diabetes treated with insulin. Diabet Med 10: 231–237,1993 sourceNot checked yet

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In that survey, the prevalence of hypoglycemia rose with escalating therapeutic requirements, with the highest rate associated with insulin.

“The prevalence of hypoglycemia rose with escalating therapeutic requirements, with the highest rate being associated with insulin.”

• cites [76] Miller CD, Philips LS, Ziemer DC, Gallina DL, Cook CB, El-Kebbi IM: Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 161: 1653–1659,2001 sourceNot checked yet

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In a multicenter, double-blind, controlled trial in Europe comparing modified release gliclazide with glimepiride over 6 months, both groups achieved a reduction of A1C of around 1.0%, with fewer patients reporting hypoglycemia with modified release gliclazide (3.7%) compared with glimepiride (8.9%), and severe hypoglycemia did not occur.

“Both groups achieved a reduction of A1C of around 1.0%, with fewer patients reporting hypoglycemia with modified release gliclazide (3.7%) compared with glimepiride (8.9%).Severe hypoglycemia did not occur.”

• cites [123] Schernthaner G, Grimaldi A, Di Mario U, Drzewoski J, Kempler P, Kvapil M, Novials A, Rottiers R, Rutten GEHM, Shaw KM, the GUIDE Study: Double blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest 34: 535–542,2004 sourceNot checked yet

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The oral glucose prandial regulators, repaglinide and nateglinide, are insulin secretagogues that have a rapid onset of action but do not stimulate insulin secretion in the fasting state and provoke less hypoglycemia than the sulfonylureas.

“The oral glucose prandial regulators, repaglinide and nateglinide, are insulin secretagogues that have a rapid onset of action but do not stimulate insulin secretion in the fasting state and provoke less hypoglycemia than the sulfonylureas (124 -127).”

• cites [124] Strange P, Schwartz SL, Graf RJ, Polvino W, Weston I, Marbury TC, Huang WC, Goldberg RB: Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes. Diabetes Technol Ther 1: 247–256,1999 sourceNot checked yet

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• cites [125] Kristensen JS, Frandsen KB, Bayer T, Muller P: Compared with repaglinide, sulfonylurea treatment in type 2 diabetes is associated with a 2.5-fold increase in symptomatic hypoglycemia with blood glucose levels &lt;45 mg/dl (Abstract). Diabetes 49 (Suppl. 1): A131,2000 sourceNot checked yet

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• cites [126] Kristensen JS, Frandsen KB, Bayer T, Muller P: Repaglinide treatment is associated with significantly less severe hypoglycemic events compared to sulphonylurea. Diabetologia 42 (Suppl. 1): A4,1999Not checked yet

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• cites [127] Culy CR, Jarvis B: Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 61: 1625–1660,2001 sourceNot checked yet

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In most cases, the severe hypoglycemia had occurred within 1 month of commencing glipizide and was not related to dose, suggesting that the response was idiosyncratic.

“In most cases, the severe hypoglycemia had occurred within 1 month of commencing the drug and was not related to dose, suggesting that the response was idiosyncratic.”

• cites [116] Asplund K, Wilholm B-E, Lundman B: Severe hypoglycaemia during treatment with glipizide. Diabet Med 8: 726–731,1991 sourceNot checked yet

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Risk factors for severe hypoglycemia in people with type 2 diabetes treated with sulfonylureas include age, a past history of vascular disease, renal failure, reduced ingestion of food, alcohol consumption, and interactions with other drugs.

“Risk factors for severe hypoglycemia in people with type 2 diabetes treated with sulfonylureas include age, a past history of vascular disease, renal failure, reduced ingestion of food, alcohol consumption, and interactions with other drugs (59,73,95-102).”

• cites [59] Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y: Drug-induced hypoglycemic coma in 102 diabetic patients. Arch Intern Med 159: 281–284,1999 sourceNot checked yet

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• cites [73] Akram K, Pedersen-Bjergaard U, Borch-Johnsen K, Thorsteinsson B: Recall of severe hypoglycaemic episodes and course of hypoglycaemia awareness in insulin treated type 2 diabetes in one year follow-up (Abstract). Diabetologia 46 (Suppl. 2): A304,2003Not checked yet

  Not checked in the free run.

• cites [95] Asplund K, Wilholm B-E, Lithner F: Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia 24: 412–417,1983 sourceNot checked yet

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• cites [96] Hartling SG, Faber OK, Wegmann M-L, Wahlin-Boll E, Melander A: Interaction of ethanol and glipizide in humans. Diabetes Care 10: 683–686,1987 sourceNot checked yet

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• cites [97] Seltzer HS: Drug-induced hypoglycemia: a review of 1418 cases. Endocrinol Metab Clin North Am 18: 163–183,1989 sourceNot checked yet

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• cites [98] Campbell IW: Hypoglycaemia and type 2 diabetes: sulphonylureas. In Hypoglycaemia and Diabetes: Clinical and Physiological Aspects. Frier BM, Fisher BM, Eds. London, Edward Arnold,1993, p. 387–392Not checked yet

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• cites [99] Campbell IW, Chalmers J, Herlihy OM: Sulphonylurea-induced hypoglycaemia in elderly people with diabetes. Practical Diabetes 11: 102–103,1994 sourceNot checked yet

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• cites [100] Burge MR, Zeise T-M, Sobhy TA, Rassam AG, Schade DS: Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose. Diabetes Care 22: 2037–2043,1999 sourceNot checked yet

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• cites [101] Tattersall RB: Frequency, causes and treatment of hypoglycaemia. In Hypoglycaemia in Clinical Diabetes. Frier BM, Fisher BM, Eds. Chichester, U.K., John Wiley and Sons,1999, p. 55–88Not checked yet

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• cites [102] Harrigan RA, Nathan MS, Beattie P: Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity and treatment. Ann Emerg Med 38: 68–78,2001 sourceNot checked yet

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Improvements in insulin resistance persist for up to 16 h after the period of activity, thus exposing the individual to a continuing risk of hypoglycemia.

“Improvements in insulin resistance persist for up to 16 h after the period of activity (91), thus exposing the individual to a continuing risk of hypoglycemia.”

• cites [91] Devlin JT, Hirshman M, Horton ED, Horton ES: Enhanced peripheral and splanchnic insulin sensitivity in NIDDM men after single bout of exercise. Diabetes 36: 434–439,1987 sourceNot checked yet

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Glimepiride, a long-acting sulfonylurea, may partly fulfil the role of a sulfonylurea with good glycemic control and low risk of hypoglycemia as it has a lower affinity for the β-cell receptor than glyburide, and its insulin secretory capacity is lower in both the fasting and postprandial states.

“Glimepiride, a long-acting sulfonylurea, may partly fulfil this role as it has a lower affinity for the ␤-cell receptor than glyburide (117), and its insulin secretory capacity is lower in both the fasting (118) and postprandial (119) states.”

• cites [117] Muller G, Hartz D, Punter J, Okonomopulos R, Kramer W: Differential interaction of glimepiride and glibenclamide with the β-cell-sulfonylurea receptor: binding characteristics. Biochim Biophys Acta 1191: 267–277,1994 sourceNot checked yet

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• cites [118] Draeger KE, Wernicke-Panten K, Lomp H-J, Schuler E, Rosskamp R: Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl): a double-blind comparison with glibenclamide. Horm Metab Res 28: 419–425,1996 sourceNot checked yet

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• cites [119] Raptis SA, Hatziagelaki E, Dimitriadis G, Draeger KE, Pfeiffer C, Raptis AE: Comparative effects of glimepiride and glibenclamide on blood glucose, C-peptide and insulin concentrations in the fasting and postprandial state in normal man. Exp Clin Endocrinol Diabetes 107: 350–355,1999 sourceNot checked yet

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The frequency of hypoglycemia is lower in people treated with sulfonylureas than in those treated with insulin but is probably underestimated.

“The frequency of hypoglycemia is lower in people treated with sulfonylureas than in those treated with insulin (2,76,79) but is probably underestimated (104).”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

  Not checked in the free run.

• cites [76] Miller CD, Philips LS, Ziemer DC, Gallina DL, Cook CB, El-Kebbi IM: Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 161: 1653–1659,2001 sourceNot checked yet

  Not checked in the free run.

• cites [79] Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, Frier BM, Morris AD, the DARTS/MEMO Collaboration: Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care 26: 1176–1180,2003 sourceNot checked yet

  Not checked in the free run.

• cites [104] Ferner RE, Neil HAW: Sulphonylureas and hypoglycaemia. Br Med J 296: 949–950,1988 sourceNot checked yet

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May combine two claims.

Glyburide is associated with significantly more episodes of severe hypoglycemia than gliclazide because its hypoglycemic effects last for 24 h as a consequence of the presence of active metabolites.

“Glyburide is associated with significantly more episodes of severe hypoglycemia than gliclazide (112) because its hypoglycemic effects last for 24 h (111) as a consequence of the presence of active metabolites (111,113).”

• cites [112] Tessier D, Dawson K, Tetrault JP, Bravo G, Meneilly GS: Glibenclamide versus gliclazide in type 2 diabetes of the elderly. Diabet Med 11: 974–980,1994 sourceNot checked yet

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• cites [111] Rendell M: The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 64: 1339–1358,2004 sourceNot checked yet

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• cites [113] Jonsson A, Chan JC, Rydberg T, Vaaler S, Hallengren B, Cockram CS, Critchley JA, Melander A: Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian and Chinese patients with type-2 diabetes. Eur J Clin Pharmacol 55: 721–727,2001 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In patients with renal impairment, glimepiride can cause prolonged hypoglycemia, but it is thought to be safer than other sulfonylureas.

“In patients with renal impairment, glimepiride can cause prolonged hypoglycemia (121), but it is thought to be safer than other sulfonylureas (122).”

• cites [121] Veitch PC, Clifton-Bligh RJ: Long-acting sulphonylureas: long-acting hypoglycemia. Med J Australia 180: 84–85,2004 sourceNot checked yet

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• cites [122] Rosenkranz B, Profozic V, Metalko Z, Mrzljak V, Lange C, Malerczyk V: Pharmacokinetics and safety of glimepiride at clinical doses in diabetic patients with renal impairment. Diabetologia 39: 1617–1624,1996 sourceNot checked yet

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May combine two claims.

Alcohol impairs counterregulatory responses to hypoglycemia in type 1 diabetes but does not appear to delay recovery from hypoglycemia in type 2 diabetes.

“Alcohol impairs counterregulatory responses to hypoglycemia in type 1 diabetes (93) but does not appear to delay recovery from hypoglycemia in type 2 diabetes (94).”

• cites [93] Avogaro A, Beltramello P, Gnudi L, Maran A, Valerio A, Miola M, Marin N, Crepaldi C, Confortin L, Costa F: Alcohol intake impairs glucose counterregulation during acute insulin-induced hypoglycemia in IDDM patients: evidence for a critical role of free fatty acids. Diabetes 42: 1626–1634,1993 sourceNot checked yet

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• cites [94] Rasmussen BM, Orskov L, Schmitz O, Hermansen K: Alcohol and glucose counterregulation during acute insulin-induced hypoglycaemia in type 2 diabetic subjects. Metabolism 50: 451–457,2001 sourceNot checked yet

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May combine two claims.

In a population-based study in Germany, of 145 episodes of severe hypoglycemia treated in patients with type 2 diabetes attending a hospital emergency department over 4 years, 45 patients were receiving sulfonylureas; glimepiride was implicated in 6 episodes compared with 38 severe events associated with glyburide.

“A total of 145 episodes of severe hypoglycemia were treated, and 45 of these patients were receiving treatment with sulfonylureas.Although glimepiride had been prescribed more frequently than glyburide, it was implicated in 6 episodes of severe hypoglycemia, compared with a total of 38 severe events associated with glyburide.”

• cites [120] Holstein A, Plaschke A, Egberts E-H: Lower incidence of severe hypoglycemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 17: 467–473,2001 sourceNot checked yet

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May combine two claims.

The risk of hypoglycemia of each sulfonylurea relates to its pharmacokinetic properties and is highest with long-acting sulfonylureas such as chlorpropamide, glyburide (glibenclamide), and long-acting glipizide.

“The risk of hypoglycemia of each sulfonylurea relates to its pharmacokinetic properties (104 -108) and is highest with long-acting sulfonylureas such as chlorpropamide, glyburide (glibenclamide), and long-acting glipizide (101,109 -111).”

• cites [104] Ferner RE, Neil HAW: Sulphonylureas and hypoglycaemia. Br Med J 296: 949–950,1988 sourceNot checked yet

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• cites [105] DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131: 281–303,1999 sourceNot checked yet

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• cites [106] Davis TM, Daly F, Walsh JP, Ilett KF, Beilby JP, Dusci LJ, Barrett PH: Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes. Br J Clin Pharmacol 49: 223–230,2000 sourceNot checked yet

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• cites [107] Harrower A: Gliclazide modified release: from once-daily administration to 24-hour blood glucose control. Metabolism 49 (Suppl. 2): 7–11,2000 sourceNot checked yet

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• cites [108] Schernthaner G: Gliclazide modified release: a critical review of pharmacodynamic, metabolic and vasoprotective effects. Metabolism 52 (Suppl. 1): 29–34,2003 sourceNot checked yet

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• cites [101] Tattersall RB: Frequency, causes and treatment of hypoglycaemia. In Hypoglycaemia in Clinical Diabetes. Frier BM, Fisher BM, Eds. Chichester, U.K., John Wiley and Sons,1999, p. 55–88Not checked yet

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• cites [109] Stahl M, Berger W: Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 16: 586–590,1999 sourceNot checked yet

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• cites [110] Del Prato, Aragona M, Coppelli A: Sulfonylureas and hypoglycaemia. Diabetes Nutr Metab 15: 444–451,2002Not checked yet

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• cites [111] Rendell M: The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 64: 1339–1358,2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Hypoglycemia is not a common side effect of treatment with metformin, thiazolidinediones, or α-glucosidase inhibitors, although it has been occasionally reported in association with metformin when food intake is limited.

“Hypoglycemia is not a common side effect of treatment with metformin, thiazolidinediones, or ␣-glucosidase inhibitors, although it has been occasionally reported in association with metformin when food intake is limited (2,103).”

• cites [2] United Kingdom Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–852,1998 sourceNot checked yet

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• cites [103] United Kingdom Prospective Diabetes Study Group: A 6 year randomised controlled trial comparing sulfonylurea, insulin and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy (UKPDS 24). Ann Intern Med 128: 165–175,1998 sourceNot checked yet

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May combine two claims.

Hypoglycemia occurs most frequently with insulin therapy, but sulfonylurea-induced hypoglycemia is also a significant problem.

“It occurs most frequently with insulin therapy, but sulfonylurea-induced hypoglycemia is also a significant problem.”

May combine two claims.

In separate double-blind, randomized, 1-year studies comparing repaglinide with glipizide, gliclazide, and glyburide, mean A1C concentrations did not differ between any of the treatment groups, and in all sulfonylurea groups the prevalences of hypoglycemia (3.3%) were comparable; in the repaglinide group the prevalence of hypoglycemia was 1.3% with equivalent glycemic control.

“Mean A1C concentrations did not differ between any of the treatment groups, and in all sulfonylurea groups the prevalences of hypoglycemia (3.3%) were comparable.In the repaglinide group the prevalence of hypoglycemia was 1.3% with equivalent glycemic control.”

• cites [125] Kristensen JS, Frandsen KB, Bayer T, Muller P: Compared with repaglinide, sulfonylurea treatment in type 2 diabetes is associated with a 2.5-fold increase in symptomatic hypoglycemia with blood glucose levels &lt;45 mg/dl (Abstract). Diabetes 49 (Suppl. 1): A131,2000 sourceNot checked yet

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• cites [126] Kristensen JS, Frandsen KB, Bayer T, Muller P: Repaglinide treatment is associated with significantly less severe hypoglycemic events compared to sulphonylurea. Diabetologia 42 (Suppl. 1): A4,1999Not checked yet

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• cites [127] Culy CR, Jarvis B: Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 61: 1625–1660,2001 sourceNot checked yet

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May combine two claims.

In older people, effective self-treatment of hypoglycemia may be compromised by the juxtaposition of the glycemic thresholds for onset of symptoms and cognitive dysfunction, which occur almost simultaneously, and these age-related changes will be relevant to many people with type 2 diabetes.

“In older people, effective self-treatment of hypoglycemia may be compromised by the juxtaposition of the glycemic thresholds for onset of symptoms and cognitive dysfunction, which occur almost simultaneously, and these age-related changes will be relevant to many people with type 2 diabetes.”

May combine two claims.

In a randomized trial of 121 male participants with type 2 diabetes, CSII was compared with multiple dose insulin; comparable glycemic control was obtained with both regimens, with a lower incidence of mild hypoglycemia in the CSII group (28.4 vs. 9.5 events per patient-year, P < 0.001), although no effect was observed on the incidence of severe hypoglycemia.

“Comparable glycemic control was obtained with both regimens, with a lower incidence of mild hypoglycemia in the CSII group (28.4 vs. 9.5 events per patient-year, P Ͻ 0.001) (141), although no effect was observed on the incidence of severe hypoglycemia.”

• cites [141] Saudek CD, Duckworth WC, Giobie-Hurder A, Henderson WG, Henry RR, Kelley DE, Edelman SV, Zieve FJ, Adler RA, Anderson JW, Anderson RJ, Hamilton BP, Donner TW, Kirkman MS, Morgan NA: Implantable insulin pump versus multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomised clinical trial: Department of Veterans Affairs Implantable Insulin Pump Study Group. JAMA 276: 1322–1327,1996 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

With progressive insulin deficiency, people with type 2 diabetes develop counterregulatory deficiencies and impaired symptomatic awareness, similar to type 1 diabetes.

“With progressive insulin deficiency, people with type 2 diabetes develop counterregulatory deficiencies and impaired symptomatic awareness, similar to type 1 diabetes.”

May combine two claims.

Glimepiride, modified release gliclazide, and the prandial glucose regulators may also limit hypoglycemia risk.

“Glimepiride, modified release gliclazide, and the prandial glucose regulators may also limit hypoglycemia risk.”

May combine two claims.

In insulin-treated type 2 diabetes, the frequency of hypoglycemia must not be underestimated, particularly in the elderly, in whom the morbidity of hypoglycemia poses particular problems, and the mortality may be unrecognized.

“In insulin-treated type 2 diabetes, the frequency of hypoglycemia must not be underestimated, particularly in the elderly, in whom the morbidity of hypoglycemia poses particular problems, and the mortality may be unrecognized.”

May combine two claims.

In a 6-month randomized trial of 299 participants with type 2 diabetes, inhaled insulin was compared with subcutaneous insulin; glycemic control was comparable and inhaled insulin was associated with a relative risk of all hypoglycemia of 0.89 (95% CI 0.82-0.97) when compared with subcutaneous insulin.

“Glycemic control was comparable and inhaled insulin was associated with a relative risk of all hypoglycemia of 0.89 (95% CI 0.82-0.97)when compared with subcutaneous insulin (143).”

• cites [143] Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, Chaisson J-L, Levin SR, the Exubera Phase III Study Group: Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes. Diabetes Care 27: 2356–2362,2004 sourceNot checked yet

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May combine two claims.

Although glucagon-like peptide-1 analogs may provoke reactive hypoglycemia in nondiabetic volunteers, they do not appear to cause hypoglycemia in people with type 2 diabetes.

“Although they may provoke reactive hypoglycemia in nondiabetic volunteers (149), they do not appear to cause hypoglycemia in people with type 2 diabetes (150,151).”

• cites [149] Meier JJ, Nauck MA: Glucagon-like peptide 1 (GLP-1) in biology and pathology. Diabetes Metab Res Rev 21: 91–117,2005 sourceNot checked yet

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• cites [150] Vilsbøll T, Krarup T, Madsbad S, Holst JJ: No reactive hypoglycemia in type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose. Diabetes Care 18: 144–149,2001 sourceNot checked yet

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• cites [151] Knop FK, Vilsbøll T, Larsen S, Madsbad S, Holst J, Krarup T: No reactive hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis. Diabetes Care 26: 2581–2587,2003 sourceNot checked yet

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

Analogs of glucagon-like peptide-1 are associated with improvements in glycemic control.

“Analogs of glucagon-like peptide-1 are associated with improvements in glycemic control (144 -148).”

• cites [144] Zander M, Madsbad S, Madsen JL, Holst JJ: Effect of 6-week course of glucagon-like peptide 1 on glycemic control, insulin sensitivity and beta-cell function in type 2 diabetes: a parallel group study. Lancet 359: 824–830,2002 sourceNot checked yet

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• cites [145] Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD: Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 26: 2370–2377,2003 sourceNot checked yet

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• cites [146] Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bisack TA, Taylor K, Kim D, Aisporna M, Want Y, Baron AD: Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 88: 3082–3088,2003 sourceNot checked yet

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• cites [147] Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR, the NN2211–1310 International Study Group: Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog Liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 27: 1335–1342,2004 sourceNot checked yet

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• cites [148] Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O: One week’s treatment with the long-acting glucagon-like peptide-1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and α- and β-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 53: 1187–1194,2004 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Blood glucose thresholds are influenced by glycemic control, and when A1C is reduced with insulin therapy, they are shifted to lower blood glucose levels.

“Blood glucose thresholds are influenced by glycemic control, and when A1C is reduced with insulin therapy, they are shifted to lower blood glucose levels.”

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

Variations in study design, heterogeneity of study populations, and differing definitions of hypoglycemia have confounded attempts to derive accurate overall figures for the frequency of hypoglycemia in type 2 diabetes.

“Variations in study design, heterogeneity of study populations, and differing definitions of hypoglycemia have con-founded attempts to derive accurate overall figures for the frequency of hypoglycemia in type 2 diabetes.”

May combine two claims.

The use of insulin analogs may limit, but does not eradicate, the risk of hypoglycemia.

“The use of insulin analogs may limit, but does not eradicate, the risk of hypoglycemia.”

May combine two claims.

Few studies of hypoglycemia in people with type 2 diabetes have addressed the potential effects of ageing per se, but the available evidence suggests that it modifies the counterregulatory and symptomatic responses to hypoglycemia.

“Few studies of hypoglycemia in people with type 2 diabetes have addressed the potential effects of ageing per se, but the available evidence suggests that it modifies the counterregulatory and symptomatic responses to hypoglycemia.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

Hypoglycemia has been considered to be a mild and infrequent side effect of treatment in type 2 diabetes, but insufficient and misleading information may have encouraged this misperception.

“Hypoglycemia has been considered to be a mild and infrequent side effect of treatment in type 2 diabetes, but insufficient and misleading information may have encouraged this misperception.”

May combine two claims.

In a randomized multicenter trial comparing repaglinide with nateglinide, slightly lower A1C values were achieved after 16 weeks on repaglinide, but 7% of patients had experienced mild hypoglycemia compared with none in the nateglinide group.

“In a randomized multicenter trial comparing repaglinide with nateglinide, slightly lower A1C values were achieved after 16 weeks on repaglinide, but 7% of patients had experienced mild hypoglycemia compared with none in the nateglinide group (128).”

• cites [128] Rosenstock J, Hassman DR, Madder RD Brazinsky, Farrell J, Khutoryansky N, Hale PM: Repaglinide versus nateglinide monotherapy. Diabetes Care 27: 1265–1270,2004 sourceNot checked yet

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