4 Patrick AW, Bodmer CW, Tieszen KL, White MC, Williams G. Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes.
The lack of an American experience of this problem calls into question its true validity. A recent review by Gale gives several reasons why hypoglyaemic awareness may change without any contribution from human insulin. JAMES D WALKER Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Box 198 UMHC, Minneapolis, MN 55455-0385, United States 1 Teuscher A, Berger WG. Hypoglycaemia unawareness in diabetics transferred to human insulin. Lancet 1987;ii:383-5. 2 Egger M, Smith GD, Imhoof H, Teuscher A. Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study. BMJ_ 1991;303:617-2 1. (14 September.) 3 Egger M, Smith GD, Teuscher AU, Teuscher A. Influence of human insulin on symptoms and awareness of hvpoglycaemia: a randomised double blind crossover trial. BMj 1991;303:6226. (14 September.) 4 Dyer C. A case against human insulin? BMJ7 1991;303:601. (14 September.) 5 Gorden P. Human insulin and hypoglycemia. N EnglI M7ed 1990;322: 1007-8. 6 Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective counter-regulation after strict glycemic control in insulin-dependent diabetes mellitus. N Engl Med 1987;316: 1376-83. 7 Gale EAM. Hypoglycaemia and human insulin. Lancet 1989; ii: 1264-6.
SIR, -Unawareness of hypoglycaemia was a major problem long before the use of human insulin.' Of the insulin dependent patients I studied, only two out of 12 with hypoglycaemic unawareness were using human insulin.2 Before considering any possible relation with human insulin,'4 we need to explain how this condition occurs without human insulin. An association is being established between tight glycaemic control and reduced adrenergic responsiveness to hypoglycaemia.' Data are emerging to suggest that it may be hypoglycaemia itself which leads to hypoglycaemic unawareness.6 Our own data,' confirming that of others,' suggest that patients with inadequate hypoglycaemic counterregulation produce reduced adrenaline and pancreatic polypeptide during hypoglycaemia, and this reflects reduced responsiveness of a central glucoregulatory centre.' The possibility emerges that frequent mild hypoglycaemia, which may particularly occur with tight diabetic control, leads to an obtunded responsiveness of such a central glucoregulatory centre, the consequent lack of autonomic activity during hypoglycaemia causing the development of hypoglycaemic unawareness. The Eli Lilly data sheet suggests that transfer from animal to human insulin may require a dose reduction.8 This highlights the likelihood that subcutaneous absorption of human insulin is slightly different from animal insulin. Egger and colleagues' patients were experiencing "about one mild hypoglycaemic episode a week" before the study.4 This might reflect more frequent unrecognised milder hypoglycaemic episodes. Thus if frequent hypoglycaemia causes hypoglycaemic unawareness Egger et al's patients would be particularly susceptible to the development ofthis problem. As only 18 of their 44 patients were already using human insulin a greater number would have been disturbed from their status quo by the introduction of human insulin than by the introduction of porcine insulin. If human insulin is absorbed slightly more quickly, the subtle overall change in pattern of glycaemic control caused by its introduction in this majority of patients using porcine insulin could have accounted for the result. If this theory is correct a routine small dose reduction accompanying the change from animal to human insulin would reduce its apparent association with hypoglycaemic unawareness; conversely, a study in which a majority of patients were converted from human to porcine insulin with a slight dose increase might generate an apparent association between porcine insulin and hypoglycaemic unawareness. A recent study found
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that patients stable on animal and human insulins were similar with respect to hypoglycaemic symptoms and frequency of coma.9 R E J RYDER Department of Diabetes, Endocrinology, and Lipid Metabolism, ' Dudley Road Hospital, Birmingham B 18 7QH 1 Lawrence RD. Insulin hvpoglvcaemia. Changes in nervous manifestations. Lancet 1941 ;ii:602. 2 Ryder REJ, Owens DR, Ghatei MA, Bloom SR, Hayes TM. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation to diabetic autonomic neuropathy. BAt] 1990;301:783-7. 3 Egger M, Davey Smith CJ, Imhoof H, Teuscher A. Risk of severe hypoglvcaemia in insulin treated diabetic patients transferred to human insulin: a case control studv. B.M 1991;303:617-21. (14 September.) 4 Egger M, Davey Smith G, Teusclter AU, Teuscher A. Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. BMJ7 1991;303: 622-6. (14 September.) 5 Amiel SA, ramborlane WV, Simonson DC, Sherwin RS. Defectiv-e glucose counterregulation after strict glycaemic control of insulin-dependent diabetes mellitus. N Engl 7 Med 1987;316: 1376-83. 6 Heller SR, Cryer PE. Does hypoglycaemia cause hypoglycaemia unawareness? Diabetic Med 1990;7(suppl 2): IA. 7 White NH, Gingerich RL, Levandoski LA, Cryer PE, Santiago JV'. Plasma pancreatic polypeptide response to insulin induced hvpoglvcaemia as a marker for defective glucose counterregulation in insulin dependent diabetes melitus. Diabetes 1985;34:870-5. 8 Association of the British Pharmaceutical Industry. ABPI Data Sheet Compendium 1990-1991. London: Datapharm, 1991: 907-10. 9 Muhlhauser I, Heinnemann L, Fritsche E, von Lennep K, Berger M. Hypoglycaemic symptoms and frequency of severe hypoglycaemia in patients treated with human and animal insulin preparations. Diabetes Care 1991;14:745-9.
SIR,-Matthias Egger and colleagues report on transferring patients to human insulin. 2 The group in Berne was largely responsible for initiating the concern about hypoglycaemia and human insulin3; this concern has attracted widespread media attention, and mass legal action is threatened even though several other carefully controlled scientific studies have failed to show any clear differences in responses during hypoglycaemia induced by insulins of different species. The original report was widely criticised, and considerable caution must be exercised in interpreting the current studies too. The case-control study can be valid only if patients in the control group were matched precisely to index patients.' Yet the control group included patients with malignant disease in hospital, patients with cardiovascular emergencies, and even a group admitted to hospital for regulation of diabetic control (which by definition must be hyperglycaemia). This diverse group of subjects hardly seems a reasonable match for a cohort of otherwise well diabetic patients who happen to have an episode of severe hypoglycaemia. Indeed, even the index group was heterogeneous, including, we assume, several insulin treated patients with non-insulin dependent diabetes mellitus with appreciable residual insulin secretion. Several of the index patients experienced recurrent episodes of hypoglycaemia, and glycaemic control was significantly better in the index group than the control group. This is well known to predispose to hypoglycaemia and loss of hypoglycaemic awareness. Although an association between hypoglycaemia and human insulin was still evident after multivariate analysis, whether this was due to the human insulin itself or individual factors, such as inappropriate treatment regimens, is impossible to determine. The possibility that it might have been due to inappropriate treatment regimens is particularly relevant here as some 40% of both index and control patients were treated with a single daily insulin injection. In the second study the authors claim, based on their findings that patients receiving human insulin were more likely to report symptoms of neuroglycopenia, that a qualitative difference in symptoms may prevent recognition of hypoglycaemia in time to take appropriate corrective
action.2 This proposal is not supported by the data presented as only one episode of hypoglycaemic coma occurred during treatment with human insulin and two during treatment with porcine insulin. It is also of note that over a quarter of all episodes of reported hypoglycaemia had to be excluded from analysis because the prevailing blood glucose concentration was not in the hypoglycaemic range. This highlights a potential problem in such field studies that depend on self reporting of symptoms as even experienced patients clearly can have difficulty identifying hypoglycaemia, irrespective of the insulin species used. As only a few patients are affected (in the United Kingdom at least) the way forward is surely to perform carefully controlled scientific studies in patients specifically reporting loss of awareness of hypoglycaemia when changed from animal to human insulins. To our knowledge, only one such study has been done4; it found no differences in symptoms or counterregulatory hormone responses during hypoglycaemia induced by human and porcine soluble insulin. If affected patients are as common in Switzerland as the work of the Berne group suggests the group should be able to test its hypothesis easily in a rigorously controlled setting, rather than simply adding to the existing confusing reports. ALAN W PATRICK GARETH WILLIAMS
University Department of Medicine, University of Liverpool, PO Box 147, Liverpool L69 3BX I Egger M, Davey Smith G, Imhoof H, Teuscher A. Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study. BMJ 1991;303:617-21. (14 September.) 2 Egger M, Davey Smith G, Teuscher AU, Teuscher A. Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial. BMJ 1991;303:622-6. (14 September.) 3 Teuscher A, Berger WG. Hypoglycaemia unawareness in diabetics transferred from beef/porcine to human insulin. Lancet 1987;ii:382-5. 4 Patrick AW, Bodmer CW, Tieszen KL, White MC, Williams G. Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes. Lancet 1991;338: 528-32.
SIR, -The report by Matthias Egger and colleagues implies a qualitative shift in the range of reported symptoms and not an absolute change to either neuroglycopenic or autonomic symptoms during treatment with a particular insulin species. It does not address the issue of unawareness of hypoglycaemia.' Perception of the onset of hypoglycaemia depends on neither the number nor even the nature of hypoglycaemic symptoms. One symptom of profound intensity may provide greater warning of the onset of hypoglycaemia than five symptoms of low intensity. Assessment of symptoms' intensity is fundamental to identifying any change in perception of hypoglycaemia, and the possibility that an increase in the number of neuroglycopenic symptoms might actually heighten awareness of hypoglycaemia has not been considered. Although glycaemic thresholds for autonomic and neuroglycopenic symptoms differ in normal subjects,2 diabetic patients with normal awareness of hypoglycaemia report neuroglycopenic symptoms more commonly at the onset of hypoglycaemia,3 recognising these as their initial warning cues, so that a predominance of neuroglycopenic symptoms does not equate with inability to perceive hypoglycaemia. To state that neuroglycopenic symptoms are strongly associated with an increased risk of recurrent severe hypoglycaemia while autonomic symptoms are protective' is pure conjecture. Chronic acquired unawareness of hypoglycaemia in diabetic patients is a major risk factor for severe hypoglycaemia4 and is also associated with an altered symptom profile.' This raises the important
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question of how many of the diabetic patients in Dr Egger and colleagues' crossover study had reduced awareness of hypoglycaemia before their inclusion in the study. The patients had had diabetes for a mean of over 15 years; at least a quarter could therefore be expected to have some degree of unawareness of hypoglycaemia,6 and it is pertinent that 12 patients had a history of recurrent hypoglycaemic coma. If some of these patients had altered awareness of hypoglycaemia their preexisting modified symptom profile may have biased the results. The authors suggest that the fewer reported episodes of hypoglycaemia during treatment with human insulin implied that this insulin species had impaired recognition of hypoglycaemia. The ratios of blood glucose concentrations below 2-8 mmol/l during treatment with human versus porcine insulin (1:1 14) and of completed questionnaires during treatment with these insulins (1:1 1), however, attest to the conclusion that fewer episodes of hypoglycaemia had actually occurred. A lower frequency of hypoglycaemia of unchanged severity with human insulin suggests that an altered symptom profile is likely to be of limited importance. Their extrapolation to conclude that the risk of severe hypoglycaemia with human insulin will be increased by the modified pattern of hypoglycaemic symptoms is not justified. Less than 10% of episodes of severe hypoglycaemia are treated in hospital, so that the patients who were surveyed in their case-control study may represent an atypical group. Among the patients with hypoglycaemia treated in hospital glycaemic control was better in those treated with human insulin. Treatment that vigorously tightens glycaemic control increases the frequency of severe hypoglycaemia4 and reduces symptomatic awareness.8 Thus the increased incidence of severe hypoglycaemia in patients taking human insulin may reflect overzealous diabetic control and be unrelated to insulin species. The diabetic patients in the Swiss canton of Berne were apparently converted to human insulin by pharmacists and not under careful medical supervision. Assuming that the transfer from animal to human insulin was made at equivalent dosage, the altered pharmacokinetics and immunogenicity of human insulin would predispose to lower blood glucose concentrations and increase the risk of hypoglycaemia secondary to increased bioavailability of human insulin.9 Because of an expected reduction in insulin requirement after transfer from animal to human insulin diabetic patients in the United Kingdom were instructed to reduce their dose of insulin by at least 10%, and few subsequently experienced increased hypoglycaemia. Although the progressive rise in the frequency of severe hypoglycaemia in Berne occurred in parallel with the increasing use of human insulin,, this simultaneous rise does not necessarily impute a causal relation. We submit, therefore, that neither of Dr Egger and colleagues' papers' indicates a relation between human insulin and a putative loss of awareness of hypoglycaemia in diabetic patients. BRIAN M FRIER KENNETH M MAcLEOD DAVID A HEPBURN
Department of D)iabetes, Royal Infirmary of Edinburgh, Edinburgh EH3 9YW I Egger M, Davey Smith G, l'tescher AU, Tcuscher A. Influencc of human insulin on symptoms anid awarcness of hypoglycaemia: a randomised double blind crossover trial. B.id 1991;303:622-6. (14 September.) 2 Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen 1, Kiss 1, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cercbral dysfunction.
AmJ Physiol 1991;260:E67-74. 3 Hepburn DA, Deary IJ, Frier BM, IPatrick AW, Quin JID, Fisher BM. Acute insulin-induced hypoglycemia in humans with and without type 1 (insulin-dependent) diabetes: factoranalysis approach. Diabetes Care (in press). 4 Diabetes Control and Complications Trial Research Group.
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Epidemiology of ses ere hvpoglycemia in the diabetes control and complications trial. A mI1ed 1991;90:450-9. Hepburn DA, Dcary I], Fricr B1\. Classification of symptoms of hypoglyvacmia in insulin-treated diabetic patients using factor analysts: relationship to hypoglycaemia unawareness. Diabetic Med (in press). Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin treated diabetic patients: presalence and relationship to autonomic neuropathy. Diatbetic 'led 1990;7:711-7. Egger M, Dasey Smith G, Imhoof H, Teuscher A. Risk of sesere hvpoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study. BMJ 1991;303:617-21. (14 September.) Lager I, Attval S, Blohme G, Smith U. Altered recognition of hypoglvcaemic symptoms in type 1 diabetes during intensified control with continuous subcutaneous insulin infusion. Diabetic Med 1986;3:322-5. Transferring diabetic patients to human insulin [editorial]. Iancet 1989;i:762-3.
SIR,-We were surprised to learn how much Swiss patients with insulin dependent diabetes differ from our patients regarding the frequency of hypoglycaemic unawareness.' In 66 patients with insulin dependent diabetes treated with porcine insulin only, whose mean age and duration of diabetes were similar to those of the Swiss patients but who had slightly higher glycated haemoglobin concentrations (mean 8-4 v 7 3%, estimated p value about 0-0002), we found that 84% (79/94) of hypoglycaemic episodes in which the blood glucose concentration was
