Transfer to Human Insulin is a Potential Risk Factor for Severe Hypoglycaemia

Matthias Egger*, George Davey Smith**, Arthur Teuscher*

* Diabetes Section, Department of Medicine, University of Berne, Inselspital, 3010 Berne, Switzerland
** Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London, UK

published in: Hypoglycaemia and Human Insulin. Editors: Konrad Federlin - Harry Keen - Hellmut Mehnert. Georg Thieme Verlag Stuttgart - New York 1991

Abstract

Prompted by the clinical observation that some patients with insulin treated diabetes mellitus had more difficulties to recognize hypoglycaemia after transfer to human insulin, a case-control study of hospital admissions for severe hypoglycaemia was performed:

Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin:
A case control study. British Medical Journal 1991; 303:617-621

The period from 1984 to 1987, when many patients were unselectedly transferred to human insulin because porcine insulin became no longer available, was investigated. Compared to animal insulin use, human insulin use was associated with a hypoglycaemia rate ratio of 2.4.

In order to investigate whether the symptom pattern associated with human insulin hypoglycaemia differed from that with porcine insulin, a prospective randomized double-blind crossover trial was subsequently performed:

Influence of human insulin on symptoms and awareness of hypoglycaemia: A randomised double blind crossover trial. British Medical Journal 1991; 303:622-626

With human insulin, patients were more likely to report neuroglycopenic symptoms such as lack of concentration, restlessness, confusion and visual disturbance, but less likely to report autonomic symptoms like hunger, tremor and sweating. Transfer to human insulin may increase the risk of severe hypoglycaemia. This may be due to the symptom pattern experienced in human insulin hypoglycaemia which could impair patients' ability to recognize hypoglycaemia.

The clinical observation that some patients had more difficulties to recognize hypoglycaemia after transfer to human insulin (1,2), and a number of episodes of severe hypoglycaemia which occurred after transfer to human insulin (I) prompted us to investigate whether transfer to human insulin carried an increased risk of severe hypoglycaemia. The prospective randomized clinical trial (RCT) has been advocated to clarify this issue (3). However, as shown in Table 1, the sample size requirements in a RCT are considerable (4,5). For example, in order to detect a 50 % increase in the risk of severe hypoglycaeinia (relative risk 1.5) when assuming that 5 % of patients experience one episode per year, approximately 2,840 patients would have to be followed up for one year. Case-control studies require smaller sample sizes (Table 1), however, they may be subject to selection bias if patients at high risk for hypoglycaemia were more likely to be transferred to human insulin (6).

Table 1.Sample size requirements in studies investigating the risk of severe hypoglycaemia during treatment with human and animal insulin.

All calculations are based on a type 1 error of 5 % and a type 2 error of 20 %.

In Switzerland this was not the case because patients were generally transferred to human insulin purely because porcine insulins were no longer available. This resulted in a rapid increase of human insulin use during the years 1986 and 1987 (Figure 1). The prescriptions gave the name of the insulin (e.g. Actrapid® or Monotard ® Novo), and when the patients attended the pharmacy to collect their insulin, they would be given the human rather than the porcine form. This period when many patients were unselectedly transferred to human insulin can only be investigated in a case-control study.

Figure 1. Percentage use of human insulin as assessed from sales data, 1984 to 1987.

A hospital based case-control study of admissions for severe hypoglycaemia to eight Bernese public hospitals between 1984 and 1987 was therefore performed. A computerized registry was used for identification of admissions for hypoglycaemia (case admissions). Control admissions were chosen among insulin treated diabetic patients admitted for a wide range of other conditions. A matched analysis, using conditional logistic regression, was performed (7). The odds ratios obtained from this analysis estimate the incidence rate ratio (8,9). As shown in Figure 2, the annual number of admissions for hypoglycaemia increased from 1984 to 1987 (p<0.00l with Chi-square test for trend in proportions). Case and control admissions were similar with respect to age, sex, diabetes duration, onset of diabetes, insulin dose, number of daily injections, and body mass index. Mean age was 51 years, mean diabetes duration was 16 years. Therapy with human insulin was more frequent among case admissions than among control admission. The relative rate estimate for human insulin as compared to animal insulin was 2.4, indicating a 2.4 fold higher rate for admissions with severe hypoglycaemia in human insulin treated patients. Other risk factors included tight glycaemic control, history of prior hypoglycaemic coma and early diabetes onset.

Figure 2. Number of admissions for hypoglycaemia (total number of admissions) to eight public hospitals, Canton of Berne, Switzerland, 1984 to 1987. p<0.001 with chi-sqare test for trend.

In order to investigate whether transfer to human insulin alters hypoglycaemia symptoms in a way that may impair recognition and appropriate response, a randomised double-blind crossover study was subsequently performed. Forty-four patients with insulin-dependent diabetes mellitus (IDDM) (mean age 36 years, mean diabetes duration 16 years) were randomised to initially receive human or highly purified porcine insulin. Twelve patients had experienced recurrent hypoglycaemic coma prior to the study. The trial lasted for 12 weeks with crossover to the other insulin after six weeks. Hypoglycaemia was defined as a blood glucose value < 2.8 mmol/l. After recovery from hypoglycaemia a standardized symptom questionnaire was completed. There were no statistically significant differences in blood glucose profiles, haemoglobin Alc levels, fructosamine levels and insulin doses between the two treatment periods. The frequencies with which symptoms appeared were investigated for treatment with human and porcine insulin. With human insulin patients were more likely to report neuroglycopenic symptoms such as lack of concentration, restlessness, confusion and visual disturbance, but less likely to report autonomic symptoms like hunger, tremor and sweating. Table 2 ranks the symptoms according to the frequency of occurrence during treatment with human and porcine insulin.

In order to investigate which symptoms may be helpful for recognition of hypoglycaemia, and which symptoms may impair awareness, the twelve patients with a history of recurrent hypoglycaemic coma were compared to the remaining 32 patients. Patients with recurrent hypoglycaemic coma were older, had a longer diabetes duration and lower levels of haemoglobin Alc and fructosamine. For this comparison, the overall symptom frequencies over both treatment periods were calculated. There were marked differences in the occurrence of hypoglycaemia symptoms between the two groups (Table 3). Lack of concentration, confusion and visual disturbance were more frequently noted by patients with a history of recurrent hypoglycaemic coma, whereas sweating, tremor and hunger were less frequently reported.

Table 2.Hypoglycaemic symptoms ranked according to frequency of occurence during treatment with human and porcine

Table 3. Hypoglycamic symptoms ranked according to frequency of occurence in patients with and without history of recurrent hypoglycaemic coma

Recurrent hypoglycaemic coma:

Conclusion

We have offered evidence that transfer to human insulin may increase the risk of severe hypoglycaemia. This may be due to the symptom pattern experienced in human insulin hypoglycaemia which is similar to the one experienced by patients with recurrent hypoglycaemic coma. Patients should be transferred to human insulin under a physician's guidance only and not in the pharmacy because their porcine preparation had been withdrawn. They should be informed about the possibility of a change in hypoglycaemia symptoms. Since human insulin in general has no advantages over highly purified porcine insulin (l0, ll), the costs and benefits of universal transfer of patients to human insulin should seriously be considered.

References

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