The Impact of the Diabetes Control and Complications Trial and Humalog Insulin on Glycohemoglobin Levels and Severe Hypoglycemia in Type 1 Diabetes

A computerized record system developed at our center was used to identify patients seen from 1 January 1993 through 31 December 1998. All subjects began insulin therapy on the day of diagnosis and remained on insulin thereafter. Most patients were seen every 3 months. The diabetes care parameters included HbA_1c values, number of injections per day, use of Humalog insulin, and number of severe hypoglycemic episodes, which were recorded in the computer database at the time of the clinic visit. A questionnaire was sent to all patients on one occasion (1998–1999) to validate the computer records of the numbers of insulin injections per day, the month and year of switching to Humalog insulin, and the number of severe hypoglycemic episodes. Patients were included in this trial only if they returned the questionnaire. Because the data were considered unreliable when the questionnaire was not returned, patients who did not return their questionnaires were not included in this study. Clinical care guidelines were similar in subjects who remained on regular insulin, compared with those who were switched to Humalog. Severe hypoglycemic events were defined (as in the DCCT) as any episode characterized by symptoms consistent with hypoglycemia in which the patient required assistance from another person or episodes in which the patient experienced either coma and/or seizure as reported by the patient or another person. Patients who had been diagnosed in the previous 12 months of any year of study were excluded, because they were probably still producing endogenous insulin. Routine C-peptide testing was not performed. The protocol was duly approved by the Colorado Multiple Institutional Review Board.

All subjects were followed prospectively from 1993 through 1998 for HbA_1c levels, severe hypoglycemic episodes, number of insulin injections per day, date of initiation of Humalog therapy, and use of the insulin pump (continuous subcutaneous insulin infusion). Dietary advice did not change during the period of study. Subjects who switched to Humalog were included only if they had used regular insulin for at least 1 year before initiating Humalog treatment (so comparable data would be available). As of December 31, 1998, 676 subjects were using Humalog and 208 subjects were not using Humalog.

The HbA_1c level was determined using the DCA 2000 method (Bayer Diagnostics, Elkhart, IN) with a normal range of 3.2–6.2% throughout the period of this study. Control HbA_1c data from 1993 through 1998 is provided in Table 1 to show that results are comparable during this period.

Statistical analyses were performed using Microsoft Excel (’97, SR-1, Redmond, WA) and later analyzed using an SAS-Stat program package (SAS Institute, Cary, NC). Descriptive statistics, including mean and SEs, were the primary analytic method. To calculate the mean HbA_1c values and the mean number of hypoglycemic events per year, the mean per subject was calculated first, and then the mean of these means was taken. Student’s t tests (Wilcoxon tests where appropriate) were used to compare HbA_1c values and hypoglycemic events over time in the same subjects. S-Plus 4.5 software was used. Longitudinal mixed effects models (subject as random effect) were used to assess the effects of intensive therapy and Humalog use on HbA_1c values using SAS PROC MIXED (SAS Institute).

A total of 11,221 visits (and HbA_1c values) were analyzed from our computerized record system. Of the 884 subjects, 49.1% were female and 50.9% were male. The mean (± SD) age at diagnosis was 12.8 ± 8.3 years, and the mean (± SD) duration of diabetes at the initial visit was 8.4 ± 8.3 years. The demographics for the four age-groups are shown in Table 2.

Longitudinal HbA_1c values showed a significant decline after the DCCT report in 1993 to 1996 (P < 0.001), primarily because of the decrease from 1993 to 1994 (Fig. 1). The decline was significant for all subjects considered together (P < 0.001) and the 5- to 12-year-old (P < 0.04) and the >18-year-old (P < 0.02) age-groups considered individually (Fig. 1). The decline was shown in the adult group only to be significantly related(P < 0.05; mixed effects longitudinal model) to increased use of multiple injections or an insulin pump. The failure of improvement in HbA_1c levels from 1995 to 1996 was primarily because of the 13- to 18-year-old group. A second decline in HbA_1c levels was observed for all four age-groups considered together (P < 0.001), and in the 5- to 12-year-old age-group (P < 0.05) considered individually, after the introduction of Humalog in 1996 (Figs. 1 and Tables 3 and 4).

HbA_1c values for the subjects were arbitrarily divided, as previously discussed (4), into four age-groups: <5, 5–12, 13–18, and >18 years of age (Fig. 1). Although the decrease in HbA_1c values was similar across all four age-groups, the average HbA_1c values varied between groups. Subjects whose ages ranged from 13 to 18 years had the highest average HbA_1c values during the study period. Subjects older than 18 years had the lowest average HbA_1c values during the same period.

A total of 676 subjects were switched to Humalog after it was introduced in September 1996. The remaining 208 subjects were not switched to Humalog through the duration of the study. When comparing the mean HbA_1c values for these two groups, there was a significant decline in HbA_1c values after 1996 for the subjects who were switched to Humalog (P < 0.001), but not for subjects who remained on regular insulin (P > 0.05). Within the Humalog group, only 5- to 12-year-old subjects showed a significant (P < 0.05) decline from 1996 to both 1997 and 1998 (Table 3). Significant differences (P < 0.01) between treatment with Humalog or regular insulin were only present in the subjects who were >18 years of age (Table 3).

Concurrent with the initial decline in HbA_1c values after 1993, there was a significant increase (P < 0.001) in the number of severe hypoglycemic episodes through 1996 (Table 4). A second decline in HbA_1c levels was observed after the introduction of Humalog in 1996; however, there was no corresponding increase in the number of severe hypoglycemic events (P = 0.26). The duration of diabetes increased during the study period and did not have an effect on the HbA_1c levels.

When the results from the two methods of data collection regarding hypoglycemia (computerized record system versus family questionnaires) were compared, they matched almost exactly for seizures and unconscious episodes. However, episodes requiring assistance were reported as higher in the family questionnaires (which were used in this report). However, this is a difficult question, for families of young children, in which all episodes require assistance by another individual. Families of young children were asked to report requirement of help only if the child was not lucid during the episode.

The DCCT and other studies proved the importance of good blood glucose control in preventing eye, kidney, and nerve complications in people with both type 1 (1,2,7,8). Unfortunately, when the DCCT results were released, the only way to achieve better glucose control was more daily injections associated with more daily blood glucose tests, or the use of an insulin pump-delivery system. To the best of our knowledge, this is the first report to show a decline in HbA_1c values in a general diabetes clinic after the DCCT report. The decline in HbA_1c was most dramatic in teenagers and adults in the first year after the DCCT. These were the age-groups in which the DCCT data were shown to be applicable. Unfortunately, values leveled off between 1994 and 1996. In this study, the decline in HbA_1c values from 1993 to 1996 in adults was significantly related to the use of intensive therapy. As described in the DCCT (1), and as found in this study, the incidence of severe hypoglycemic events increased. The increase continued in 1995 and 1996, even though HbA_1c levels stabilized, presumably due to the continued attempts to lower values and the occurrence of “hypoglycemia-unawareness” with the greater duration of tighter control. The realization of the need for improved glycemic control, associated with a two- to threefold increase in severe hypoglycemic episodes, led to displeasure from both diabetes care providers (9) and patients.

Our study showed that the introduction of Humalog insulin made it possible to obtain the goal of improved blood glucose control without any further increase in severe hypoglycemic episodes. Alternative explanations for these outcomes might be the patient cohort changing during the study period, advances in glucose monitoring, insulin administration, increased familiarity with intensive diabetes management, and educational strategies. Humalog insulin resulted in lower postprandial blood glucose levels in every study in comparison with values after regular insulin (10–13). This was primarily because of higher insulin levels 30 to 90 min after injection, which closely matched food absorption. Many studies also showed a decline in severe hypoglycemic episodes (10–14), particularly during the nighttime. In addition, the frequency of hypoglycemic events in people using insulin pumps declined when Humalog was used in the pump rather than regular insulin (15–18).

Although the U.S. Food and Drug Administration initially approved Humalog only for children older than 12 years of age and adults, we and most others began using it in patients of all ages (19,20). Humalog was particularly helpful in children younger than 5 years of age with variable appetites. In toddlers with type 1 diabetes, postprandial administration of Humalog showed lower postprandial glucose excursions when compared with preprandial human regular insulin (20). In the current trial, the major reasons for not changing to Humalog insulin were the physician’s choice, insurance companies not willing to reimburse the cost of Humalog, and lower socioeconomic status.

The decline in HbA_1c levels after the introduction of Humalog occurred without an increase in the number of severe hypoglycemic episodes. Instead, a decrease in the number of severe episodes was found. This result is particularly important in young children, in whom severe episodes may result in brain damage (21,22). Patients and health care providers are more likely to accept intensive insulin therapy if it does not result in a greater risk for severe hypoglycemia (which can result in death).

As described in the DCCT (5), the 13- to 18-year age-group had the highest level of HbA_1c values. Increased insulin resistance in this age-group is one possible cause for such values (23,24). It is likely that behavior (including food choices) and psychological issues may also contribute to the higher HbA_1c values in teens. The 5- to 12-year age-group probably had lower HbA_1c values because puberty and insulin resistance were not yet present and because parents have more control and influence over diabetes care during this period. Although we only recommend HbA_1c values <9.3% in toddlers, when the brain is still growing and hypoglycemia can often not be recognized, their HbA_1c values were not as high as might have been anticipated. Clearly, the adult group consistently had the best HbA_1c values, probably because of lack of insulin resistance and better understanding of diabetes.

In conclusion, HbA_1c levels declined in all four age-groups after the DCCT. Unfortunately, in concurrence with the findings of the DCCT, the number of severe hypoglycemic episodes increased. However, a second significant decline in HbA_1c values occurred with the introduction of Humalog insulin. Fortunately, the incidence of severe hypoglycemic episodes did not increase after Humalog therapy. It will be important with future changes in care (e.g., introduction of continuous glucose monitoring) to document changes in HbA_1c levels as well as in the incidence of severe hypoglycemic events in diabetes clinic populations of all ages.

This research was supported by grant number M01 RR00069 from the General Clinical Research Centers Program, the National Centers for Research Resources, the National Institutes of Health, and the Children’s Diabetes Foundation.

These data were presented, in part, at the American Diabetes Association meeting in San Diego, California, June 1999.