Acta Med Scand 1988; 224: 257-62

Incidence of Severe Hypoglycemia and Its Causes in Insulin-treated Diabetics

ANDERS NILSSON, BO TIDEHOLM, JOHAN KALBN and PER KATZMAN From the Department of Medicine, Central Hospital, Helsingborg, Sweden

ABSTRACT'. Nilsson A, Tideholm B, Kaldn J, Katzman P (Department of Internal Medicine, General Hospital, Helsingborg, Sweden). Incidence of severe hypoglycemia and its causes in insulin-treated diabetics. Acta Med Scand 1988; 224: 25762.

In a one-year prospective study in insulin-treated diabetics, 61 episodes of severe hypo- glycemia demanding medical assistance were registered in 46 patients. The incidence of se- vere hypoglycemia was estimated at 0.07 per patient and year. Mean age (50k16.9 yr), dia- betes duration (19k11.6 yr), HbAk (7.8+1.8%) and daily insulin dose (0.63k0.23 IUkg) in these patients (SH group) did not differ from a control group matched for sex and age. How- ever, the patients in the SH group were treated with relatively less short-acting insulin than the patients in the control group (25+13.8% vs. 39+24.5%; pC0.01). This finding may indi- cate that multiple injection therapy with a higher relative amount of short-acting insulin could reduce the risk of severe hypoglycemia, provided the metabolic control is unaltered. Key words: diabetes mellitus, insulin treatment, hypoglycemia.

Hypoglycemia is a common complication in the treatment of diabetes mellitus. Minor hypo- glycemic reactions are readily accepted by the patients, but severe hypoglycemia are per- ceived as a major threat to everyday living (1).

Studies of the patient-per-year incidence of severe hypoglycemia document frequencies between 0.04 and 0.54 (2, 3). These wide discrepancies may be explained by differences in study population, criteria for severe hypoglycemia, methods of registration and, finally, the degree of metabolic control.

As the treatment of severe hypoglycemia is centralized to one emergency department in the health district of Helsingborg, a prospective study of the incidence and causes of severe hypoglycemia in the district could be performed. The investigation was carried out during one year starting on April 1, 1985.

METHODS The health district of Helsingborg serves a population of 142000. Based on drug sales and existing re- cords from the outpatient units, the number of insulin-treated patients could be estimated at 900. This includes all types of insulin-treated patients managed by the department of medicine as well as by the general practitioners. Only patients from this district were included in the study.

At an emergency call a mobile paramedic emergency unit, with a specially trained nurse, is directed to the location of the incident. In case of suspected severe hypoglycemia, blood glucose is measured using a glucose reflectance meter and treatment is given with glucose i.v. or glucagon i.m. Severe hypo- glycemia was defined as an episode of hypoglycemia demanding parenteral treatment promptly resolv- ing the symptoms. The records from the mobile unit and the emergency department were continuously checked by the investigators.

Within 3 weeks after the event, the patients were called to the diabetic ambulatory for an interview concerning previous medical history, insulin treatment and probable cause. In connection with this inter- view, postprandial blood samples were taken for subsequent analysis of HbA,, and C-peptide. HbA,, (normal range 3.&5.8%) was analyzed by an HPLC method and C-peptide by radioimmunoassay (4,5).

A control group matched for sex and age without registered severe hypoglycemia during the study period was selected from existing records at the diabetic ambulatory.

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258 A . Nilsson et al. Acta Med Sand 1988; 224

2oT

1 4

.- Q) lo+ - I

0-9 1 0 - 1 9 20-29 30-39 40-49 50-59 60-69 70-79 80-89

Years Fig. 1. The age distribution of the patients affected by severe hypoglycemia.

Statistics Statistical evaluation was performed using Student’s r-test and p<O.O5 was considered as statistically sig- nificant. All values are given as mean 2 SD unless otherwise stated.

RESULTS

A total number of 61 episodes of severe hypoglycemia were registered in 46 (28 males and 18 females) patients. Thirty-eight of these patients experienced one episode, three had two, three had three and finally two patients had four episodes. Thus, 38% of the episodes occur- red in 17% of the patients. Calculated from the estimated total number of insulin-treated pa- tients, this means a patient-per-year incidence of 0.07. No seasonal variation was seen and the episodes were randomly distributed over the day as well as over the week.

The age distribution and diabetes duration of the severe hypoglycemia (SH) group is shown in Figs. 1 and 2. The disease duration did not differ between the SH group and the control group (19+12 vs. 17+11 yr, NS). Thirty-three of the patients in the SH group had no detectable C-peptide in the blood. In four patients the C-peptide was >0.6 nmoVl. Of the pa- tients in the SH group, 13% showed signs of nephropathy at the clinical examination and 57% had signs of retinopathy.

Prior to the study, 78% of the patients in the SH group had experienced one or more episodes of severe hypoglycemia compared to 22% in the control group (p<O.OOl). Further- more, 87% of the patients in the SH group were treated with more than one daily injection

Ada Med Scand 1988; 224 Severe hypoglycemia in insulin-treated diabetics 259

0-4 10-14 1 20-24

1 30-34 40-44

5-9 15-19 25-29 35-39 45-49

Years Fig. 2. The duration of diabetes in the patients affected by severe hypoglycemia.

of insulin compared to 89% in the control group (NS). There was no statistically significant difference in the total amount of insulin given, calculated as IU per kg body weight, between the SH group and the control group (0.63f0.23 vs. 0.59+0.27). The relative amount of short-acting insulin, however, was significantly lower in the SH group as compared to the control group (25f13.8% vs. 39+24.5%, pCO.01) (Fig. 3). The HbA,, in the SH group was 7.8+1.8%, and 8.of1.5% in the control group (NS) (Table I).

The cause of severe hypoglycemia could be defined in 95% of the events at the interview. Decreased food intake (gastroenteritis included) (27%), increased physical activity (25%)

Table 1. Comparison between the control and severe hypoglycemia (SH) groups regarding treatment and frequency of earlier SH

Control SH group group Significance

Patients with earlier SH (%) 22 78 p<O.oOl Daily insulin dose

Per cent daily short-acting

HbAI, (Yo) 8.0k1.5 7.8k1.8 NS

(IUlkg b.w.) 0.59k0.27 0.63k0.23 NS

insulin 39k24.5 25k13.8 p<O.O1

260 A . Nilsson et al. Aaa Med Sand 1988; 224

STUDY GROUP

M u m acting In#r&l61X

6d Short actlng Inaulln 5953

CONTROL GROUP

Fig. 3. The relative amount (7'0) of short-acting insulin related to the total daily insulin dose in the severe hypoglycemia study group and the control group.

and alcohol consumption (13%) were the main causes. The patients themselves recognized the cause in 60% of the hypoglycemic episodes (Fig. 4). Of the patients in the SH group, 87% attended the outpatient clinic at the medical department and 57% of these were treated by a diabetologist. These figures did not differ from those of the control group.

In the subgroup of patients with more than one episode during the study period, age (40- 80 yr), diabetes duration (5-56 yr), HbAk (5.5-9.2%), daily insulin dose (0.41-0.89 IU/kg), relative amount of short-acting insulin (0-50%) and causes of severe hypoglycemia were similar as compared to the SH group as a whole. For two of them, alcohol abuse was the pre- cipitating factor every time. Two other patients had a remarkably neglecting attitude to reg- ularity in dietary habits and physical exercise. Finally, in the other four patients there were different causes of the hypoglycemic events.

DISCUSSION

The true incidence of severe hypoglycemia may be difficult to assess. This study deals with episodes demanding medical assistance. Severe hypoglycemia treated (glucagon or other- wise) by lay persons were not registered. This may contribute to an underestimation of the true incidence.

In spite of differences in study design, an incidence of severe hypoglycemia in the present study of 0.07 per patient and year is similar to that reported by Casparie & Elving (6) and Potter et al. (7). In 72% of the patients in the SH group, 6-peptide was below the detection limit of the assay indicating type I diabetes. Less than 50% of all our insulin-treated patients

Aaa Med Scand 1988; 224 Severe hypoglycemia in insulin-treated diabetics 261

4 Physical activity 25.4%

4 Dietary 27.1 %

a Alcohol 13.6%

4 Recent change of dose 8.5%

4 Effect of other medication 6.8

4 Wrong dose of insulin given 6.

a Other defined cause 6.8%

4 Unknown 5.1% Fig. 4. The causes of severe hypoglycemic episodes.

are classified as type I diabetics. Thus, the incidence of severe hypoglycemia in type I diabe- tics seems higher than in insulin-treated type I1 patients. In this respect, our findings are simi- lar to those of Casparie & Elving (6).

By a personal interview performed shortly after the episode of severe hypoglycemia, the cause could be deduced in almost every patient. This is in contrast to other studies (6, 7). Since most episodes were caused by the inability of the patients to correctly adjust their food intake and insulin dosage, it should be possible to decrease the risk of hypoglycemia by thorough education. However, in spite of careful interviewing and problem-oriented educa- tion, eight of the patients relapsed during the study period.

There seems to be a subpopulation specially prone to develop severe hypoglycemia. Thus, 78% of the patients in the SH group had been affected before the study period as compared to only 22% of the control group. The metabolic control did not differ between the two groups, which is in contrast to other reports (1,6). Circulating antibodies to insulin were not determined in this study. The total daily insulin dose was the same in the SH group and the control group, which is in agreement with other studies (1,8). We did, however, find that the SH group was treated with relatively less amount of short-acting insulin. This seems relevant. It might indicate that multiple injection regime with a lower relative amount of medium-act- ing insulin could decrease the incidence of severe hypoglycemia. In contrast to this, earlier reports suggest that a multiple injection regime is linked to increased risk of severe hypo- glycemia (3). However, in these studies, as opposed to our study, there was a concomitant im- provement in the metabolic control evaluated as HbA,,.

In conclusion, the incidence of severe hypoglycemia was estimated at 0.07 per patient and year in insulin-treated patients. Medium-acting insulin seems to be a precipitating factor for the development of severe hypoglycemia, which indicates that modem diabetes treatment with multiple injection regime using an insulin pen with higher relative amount of short-act- ing insulin may be favorable in terms of reduced risk of severe hypoglycemia, provided the metabolic control remains unaltered.

%

.8%

262 A . Nilsson et al. Acta Med Scand 1988; 224

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Received December 30, 1987. Accepted March 16, 1988.

Correspondence: Anders Nilsson, MD, Department of Medicine, Central Hospital, S-25187 Hel- singborg, Sweden.