Glucagon Underutilized Among Type 1 Diabetes Mellitus Patients in Japan

Introduction

G lucagon is used as a measure to treat severe hypoglycemia in nonhospital environments, and prescription of glucagon to type 1 diabetes mellitus (T1DM) patients is recommended in the guideline published by the Japan Diabetes Society. ¹ However, there have been no reports so far from Japan how much patients do actually possess it or have the experience of using it. Thus, we investigated the current situation of glucagon in Japan using a self-administered questionnaire to T1DM patients.

Subjects and Methods

The study was approved by the ethical committee at National Hospital Organization Kyoto Medical Center (Kyoto, Japan). We recruited 208 T1DM patients. Inclusion criteria were (1) patients had T1DM diagnosed according to the criteria of the Japan Diabetes Society, ¹ (2) patients were regularly treated at research sites, and (3) patients provided written informed consent. Exclusion criteria were (1) children under 14 years of age and (2) patients who were unable to answer the self-administered questionnaire for any reasons. The patients were treated at 16 research sites in different regions of Japan. The self-administered questionnaire was distributed and retrieved between April 2006 and October 2010.

The characteristics of the subjects were analyzed. The possession of glucagon, the experience of its usage, the preference to possess glucagon after reading what is glucagon and when it is used, and the barriers to have glucagon were investigated. Severe hypoglycemia was defined as any episode requiring external help, and hypoglycemia was defined as a blood glucose level ≤50 mg/dl (2.8 mmol/L). The influence of the modes of insulin delivery (i.e., multiple daily injections [MDI] vs. continuous subcutaneous insulin infusion [CSII]) and the types of insulin (i.e., soluble insulin analogs vs. other forms of insulin) on the history of severe hypoglycemia within 1 year was examined using Fisher's exact test.

A stepwise logistic regression analysis was performed to assess the influence of age, sex, diabetes duration, glycated hemoglobin (HbA1c) level, the history of severe hypoglycemia within 1 year, modes of insulin delivery, types of insulin, retinopathy, nephropathy, neuropathy, and the result of the Glucagon Knowledge Test on the possession of glucagon. The stepwise logistic regression analysis was also performed after limiting the analysis to 148 patients with a total daily insulin dose of ≥0.5 U/kg as the indication for insulin dependence. Neuropathy, retinopathy, and nephropathy were diagnosed according to the criteria of the Japan Diabetes Society. ¹

Results

Clinical characteristics of the subjects and the results of the self-administered questionnaire are described in Table 1. The ratio of patients who experienced severe hypoglycemia within 1 year was 16.3%, and there was no significant difference according to the modes of insulin delivery (MDI, 17.3%; CSII, 10.7%; P=0.581) and the type of insulin (soluble insulin analogs, 15.9%; other forms of insulin, 20.2%; P=0.465).

The possession rate of glucagon in T1DM subjects was 15.9%. The rate of those who had experience of using glucagon to treat severe hypoglycemia was 6.0%. The rate of preference to possess glucagon at home after reading the description of glucagon was 39.0%. The barriers to possess glucagon were diverse, and the most common answer was that the patient did not feel the need for glucagon.

The stepwise logistic regression analysis revealed that the possession of glucagon was significantly associated with results of the Glucagon Knowledge Test (odds ratio [OR]=24.1; 95% confidence interval [CI], 3.2–183.3; P=0.002) and the history of severe hypoglycemia within 1 year (OR=4.8; 95% CI, 2.0–12.0, P=0.001). However, it was not associated with age, sex, diabetes duration, HbA1c, modes of insulin delivery, types of insulin, retinopathy, nephropathy, and neuropathy. When the analysis was limited to 148 patients with a total daily insulin dose of ≥0.5 U/kg, the possession of glucagon was also associated with results of the Glucagon Knowledge Test (OR=12.8; 95% CI, 1.6–101.9; P=0.001) and the history of severe hypoglycemia within 1 year (OR=6.5; 95% CI, 2.2–19.5; P<0.001) and was not associated with the other factors described above.

Discussion

Usage of glucagon is recommended to treat severe hypoglycemia in nonhospital environments. ^1,2 However, our data showed that glucagon was surprisingly underutilized among T1DM patients in Japan.

The results of the Glucagon Knowledge Test and the history of severe hypoglycemia within 1 year were associated with the possession of glucagon. This is the first report of the glucagon possession rate in Japan, and it was much lower than those previously reported from Canada (82%), New Zealand (54%), Australia (92%), and Israel (60%). ^{3 –6}

Why glucagon was underutilized in Japan remains unclear. The age of the studied patients (older than 15 years of age) might be one factor to explain the difference from previous studies mainly performed on pediatric patients. The gap between the preference to possess glucagon and the actual possession of glucagon might indicate that the studied patients were not adequately informed of the glucagon through their physicians and diabetes educators. Another possibility is that the studied patients might enjoy relatively good access to an emergency unit in case of severe hypoglycemia compared with other countries in the world. Furthermore, only the vial form of glucagon is commercially available in Japan, and the absence of glucagon “kit” products might also be a barrier for the spread of glucagon.

On the other hand, glucagon as a measure to treat severe hypoglycemia has its own limitation. First, glucagon is used after severe hypoglycemia has once occurred and does not prevent it. Second, self-administration of glucagon by the patients themselves is practically impossible under severe hypoglycemia, and some other person must administer it. In Japan, injection by those other than healthcare providers is basically illegal, except in the case administered by the patients' family. There are reports describing the efficacy and safety of glucagon administered by healthcare providers; however, those by non-medical bystanders are not well documented. ^{7 –11} Thus, efforts to prevent severe hypoglycemia itself remain primarily important.

Conclusions

Glucagon as a measure to treat severe hypoglycemia was underutilized among T1DM patients in Japan. The possession of glucagon was associated with results of the Glucagon Knowledge Test and the history of severe hypoglycemia within 1 year. The glucagon possession rate was much lower than that in reports from other countries in the world.