Appropriate insulin dosing is critical to long-term management of type 1 diabetes. Randomized, controlled trials, such as the DCCT, have shown that intensive insulin intervention improves residual beta-cell function (7
) and reduces diabetes-related complications (12
). Residual pancreatic beta-cell function is believed to decrease glucose fluctuation and thus improves glycemic control, as measured by HbA1c (13
). However, it is less clear whether there is a clinical benefit to starting intensive intervention immediately after diagnosis and stabilization, or whether it is equally efficacious to ease a patient into therapy. Without an answer to this question, recommended starting doses for subcutaneous insulin fall within a wide range, ie, between 0.2 units/kg/day and 0.8 units/kg/day. In the present study, prescribed doses ranged from 0.3 units/kg/day to 0.75 units/kg/day, with the most commonly prescribed doses being 0.5 units/kg/day and 0.7 units/kg/day. When the data were divided into a lower dose insulin group (prescribed 0.5 units/kg/day or less) and a higher dose insulin group (prescribed greater than 0.5 units/kg/day), there was no difference between the groups with respect to the presence of DKA or comorbidities. Thus, the degree of illness did not appear to affect the choice of insulin starting doses. Age was the only factor found to influence intended starting insulin doses, with younger children being prescribed lower doses.
Interestingly, there was a significant difference between the intended TDD as recorded in physician notes and what was actually administered to the patient based on nursing records, with a significantly higher dose actually given compared with what was intended. This reflects the dynamic nature of diabetes management, in which insulin doses are adjusted according to the presence of hyper- or hypoglycemia. Based on the significant upward trend, it is likely that children prescribed a lower TDD of insulin experienced ongoing hyperglycemia, indicating a higher insulin need than predicted.
Within the broad range of prescribed insulin doses, we sought to compare insulin doses with frequency of hypoglycemic events. In the present study, hypoglycemia was defined as a blood glucose level of less than 4.0 mmol/L as measured by a glucometer (or point of care testing), which, according to the Canadian Diabetes Association Clinical Practice Guidelines (2
), requires a treatment. All events were confirmed by a point of care glucose test using either a hospital glucose meter or the patient’s meter once it was found to be accurate when compared against the laboratory value or both. All blood glucose tests were also either performed or supervised by a nurse; consequently, patient error in performing the test would be unlikely to have influenced the result. The question of frequency of hypoglycemia in the first few days after insulin initiation becomes especially important, given the transition within many paediatric centres away from long inpatient stays toward early diabetes care provision in the home, with support from medical day-treatment units. A descriptive study by Schneider (9
) that examined outpatient management of newly diagnosed paediatric diabetes patients found that an average initial dose of regular insulin of 0.3 units/kg/day yielded no hypoglycemic events in the first 24 h of treatment. In this study, the average total insulin dose one week postdiagnosis had increased to a range of 0.6 units/kg/day to 1.0 units/kg/day, and the authors stated that “no premium was attached to rapid restoration of metabolic control”. Another recent study (14
), using data from the Paediatric Quality Initiative, reviewed rates of hypoglycemia in the first two weeks after diagnosis in 1680 children with type 1 diabetes. They found that rates of hypoglycemia rose constantly from 4.8% to a maximum of 11.2% between day 2 and day 5, and then remained stable. The average daily insulin dose on day 2 was 0.79 units/kg/day. The highest average daily insulin dose was 0.91 units/kg/day on day 5, coinciding with the highest rate of hypoglycemia. Younger age, more severe disease at onset (higher HbA1c, higher blood glucose and lower pH) and higher daily insulin doses were associated with a higher risk of hypoglycemia from day 2 to day 14. This study differed from the present study in that it did not provide rates of hypoglycemia within the first 48 h. Furthermore, although they found a correlation between higher daily doses from day 2 to day 14 and hypoglycemia, they did not report on the actual starting doses or on the impact on HbA1c three to six months after diagnosis.
Our study revealed no difference between the high and low delivered TDD insulin groups with respect to hypoglycemic events within 48 h of initiation of subcutaneous insulin. In both groups, more than 85% of patients had no documented hypoglycemia. All events were mild and treated with oral glucose as per the Canadian Diabetes Association Clinical Practice Guidelines (2
). However, there was a trend for an increase in the number of hypoglycemic events occurring in the youngest age bracket. Children younger than six years of age were nearly two times more likely than those six to 10 years of age (24.1% versus 10.9%, respectively) and five times more likely than those older than 10 years of age (24.1% versus 4.5%, respectively) to experience a hypoglycemic event. This could be due to reduced endogenous insulin production in younger patients with diabetes. Studies (15
) have shown associations between age and beta-cell function, with older children demonstrating a longer course of preserved beta-cell function. Bonfanti et al (16
) demonstrated that C-peptide secretion was significantly lower in children with diabetes onset before five years of age. This could be contributing to more labile disease in this age group. The results of our study suggest that prescribing any insulin dose within the recommended range is safe, and that prescribing doses at the higher end of the range does not result in an increase in hypoglycemia. The exception to this is in children younger than six years of age, in which case it may be prudent to consider choosing a lower starting TDD, given the increased risk of hypoglycemia in that age group, combined with the fact that younger children are likely to have more trouble recognizing, communicating and self-managing a hypoglycemic event.
We attempted to describe the long-term outcomes of different starting insulin doses to determine whether higher starting doses within the first 48 h lead to better control four to six months after diagnosis. Theoretically, earlier control of blood glucose may confer less stress on the diabetic pancreas and, thus, has the potential to preserve endogenous islet cell function, leading to more stable diabetes management. As mentioned in the introduction, studies (5
) supporting this theory have been published. However, it is difficult to generalize these results to today’s patients with diabetes, because the standard of care has changed markedly over the past two decades. When the studies by Madsbad (5
) and Madsbad et al (6
) were conducted in the early 1980s, blood glucose monitoring was performed infrequently, and conventional dosing yielded high blood glucose levels compared with current standards. Today, standard insulin therapy for the control of blood glucose more closely resembles the results of Madsbad’s intensive treatment group (6
). Therefore, the question remains as to whether early, followed by ongoing, intensive blood glucose control confers a benefit to patients with respect to long-term outcomes within today’s standard of care. When we compared the lower delivered TDD group to the higher delivered TDD group, there was no difference in HbA1c at four to six months. This suggests that there is no appreciable value to using higher starting doses, especially if it leads to more frequent hypoglycemia. However, it is well recognized that, over time, intensive glycemic management mitigates the complications of diabetes, including micro- and macrovascular damage; therefore, the need to reach optimal blood glucose control remains.
The limitations of the present study include a relatively small sample size, and a retrospective design that led to exclusion of subjects whose data were incomplete. We were unable to evaluate how long it took patients to reach stable blood glucose levels, and whether this period was prolonged in those started on lower TDD insulin (which would be anticipated). There is potential for poorer quality of life in those who require weeks versus days to achieve normoglycemia, with respect to the patient experiencing hyperglycemic symptoms, and family and caregivers experiencing distress over ‘failing’ to meet target blood glucose levels. Areas for further research include the examination of potential psychological and economic effects on slower progression to normoglycemia.