An “out of the box” approach for prevention of ketoacidosis in youth with poorly controlled type 1 diabetes: combined use of insulin pump and long-acting insulin

Managing type 1 diabetes (T1D) in pediatric as well as adults remains a significant challenge for patients and caregivers. Only a minority of people living with T1D meet widely accepted glycemic goals, though it should be noted that studies with various advanced hybrid closed-loop (AHCL) using automated insulin delivery demonstrate improvement in glycemic outcomes (1). Despite the advances in technology and introduction of new insulins, up to 10% of people living with diabetes continue to experience acute episodes of diabetic ketoacidosis (DKA) after diagnosis [2]. Management of T1D includes multiple daily blood glucose assessments by continuous glucose monitoring (CGM), or by 4–6 self-monitoring finger prick tests, and insulin administration by subcutaneous multiple daily injections (MDI), or by continuous subcutaneous insulin administration by an insulin pump, which is considered the most physiologic method of insulin replacement [3]. Pump use affords the ability to administer accurate doses of insulin, adjust doses to activity, use extended boluses for food containing more fat and proteins, and improve glycemic control and quality of life [4‐6]. Recent reports have suggested that the AHCL system provides even more benefits [1, 7, 8]. However, in many countries they are still not available to most people living with diabetes due to economic status, and systems availability. Some limitations of the use of non-automated pumps have been identified from real-life data, following their extensive use among people living with T1D, including; refusal to wear the pumps constantly (mainly among adolescents, females, and those with worse glycemic control) [9], frequent local skin irritation and allergic reactions at the insertion site [5], and increased incidence of diabetic ketoacidosis (DKA) [10, 11]. DKA is the most distressing complication of pump therapy, reported to be associated with lower socioeconomic status [16], and mostly occurring due to insulin infusion set blockage, infusion site problems, and users delay in detection of those issues (e.g., misjudging prolonged hyperglycemia, prolonged suspension of insulin basal rate for physical activities) [12, 13]. When basal insulin infusion rates are interrupted among those treated with pumps and not recognized in time, the subcutaneous reserves of short-acting insulin are insufficient to prevent the metabolic processes that lead to ketogenesis. [14] This complication has been shown to be possibly fatal [15], and its occurrence is reported in association with low socioeconomic status. [16].

A few case reports have suggested using daily subcutaneous long-acting insulin instead of the basal pump rate, in addition to boluses by the pump, to prevent DKA [17‐20]. Accordingly, pediatric endocrinologists in Israel implemented this proposed combination of pump for meal boluses and corrections of hyperglycemia and long-acting insulin for basal coverage as part of clinical care among poorly controlled T1D adolescents, needing a pump for boluses, during the last decade. The aim of this multicenter study was to describe the Israeli national real-life experience of this combination modality, in prevention of DKA episodes and improving glycemic control parameters among pediatric and young adults living with T1D.

We describe a unique cohort of children and youth with T1D who used a combination modality of short-acting insulin delivered by pump for boluses only and full or partial basal replacement by subcutaneously injected long-acting insulin once daily. This approach evolved due to the need to help poorly controlled people living with T1D, who wish to use pump therapy for quality of life, and still be safe. This modality enabled them to have the benefits of spontaneity, flexibility and avoiding the need of several daily injections, while decreasing the risk of DKA.

Adolescents with poorly controlled T1D whose insulin is delivered by pumps are reportedly at increased risk for DKA episodes [10, 11], although followed by multi-disciplinary teams. Additionally, some people living with diabetes may find it distressing and inconvenient to be continuously attached to a pump, particularly during sports, water activities, sleep, and sexual intercourse. These issues were the main reported medical team and caregivers’ reasons for switching to the combination modality in our young cohort. Those challenges have been previously addressed, and several case reports described the use of supplemental subcutaneous long-acting insulin instead of the pump basal infusion. For example, Phillips et al. [17] described a 56-year-old patient who was experiencing recurrent episodes of DKA and who replaced 60% of the basal insulin with injected insulin glargine, resulting in the cessation of the DKA episodes. Aronson et al. [18] demonstrated a high safety profile of combined therapy with pump and injected insulin Degludec (50% of the basal dose) in adults with T1D who removed their pump before extended periods of exercise. Johansson et al. [20] demonstrated that partial replacement with glargine during pump treatment with Lispro protected against the development of ketosis in a group of seven adults with T1D. Alemzadeh et al. [19] reported the safety of partial basal insulin replacement with glargine in a group of 12 children with T1D treated with insulin pumps. These reports, however, involved small numbers of participants and with partial basal insulin replacement, and only one study was conducted in a pediatric population. [19].

To the best of our knowledge, our study represents the most comprehensive analysis to date of the practical use of that combined modality, including both partial and full replacement of basal insulin with injected long-acting insulin in young individuals. Our findings underscore the significance of this treatment option, even in the era of the powerful tool of AHCL systems, since a large percentage of the world population living with T1D still uses the older management fashions due to availability and financial causes. Notably, most of the indications for initiating the combined modality in our study population align with individuals who may not fit to the AHCL option, or may not agree to use it, further emphasizing its importance.

The size of our study cohort enabled us to characterize the population most likely to need that alternative modality, especially the poorly controlled adolescents, who were pubertal on physical examination (71%), and possibly those who had been diagnosed with ADHD. Pubertal stage was reported as being a risk factor for poorer outcome, even when treated with AHCL [26, 27]. ADHD, is also a known risk factor for lack of compliance, recurrent DKA episodes, and poorer glycemic control [25, 26]. However, the diagnosis of ADHD should be regarded with caution, since it had been suggested that there may be over diagnosis of ADHD worldwide [30], and even more in Israel. [31]. The prevalence of ADHD is variable, affecting 2–16% of the school aged population [28], and evidence exists that there is a 1.5 higher risk of having ADHD among people living with T1D compared with their siblings [29]; in our cohort, it was reported among 20% of participants.

As expected, glycemic control did not change with the combination modality, since the administration of insulin is not the only parameter responsible for glycemic control. It should be noted that most patients in this cohort were the more challenging population to balance (mean HbA1c of above 9%, and lower SES). The study emphasizes once again how difficult it is to improve diabetic control, and that just changing insulin administration modality is not sufficient. However, changing insulin delivery modality may change the risk for DKA episodes among the poorly controlled population with T1D.

The strength of our study lies in its novelty in describing and proving the benefit of a modality used by physicians worldwide, as an off-label option, with no evidence so far of its assumed benefit. Our study findings shed light on subjects’ characteristics, who may benefit from this modality, mainly by significantly reducing DKA episodes, while still enjoying the benefits of a pump for boluses.

There are some limitations to our study that bear mention, primarily, its retrospective design. Due to the real-life retrospective design, the protocol for the initiation of a combination modality and its education paradigm were not uniform, but rather determined and explained by the subject’s multi-disciplinary team, and the reasons for discontinuing the combined therapy are missing. Additionally, our study population is small, although nationwide, since we use this modality only as last option and for a very specific population of patients. Therefore, it was possibly not large enough to detect baseline characteristics differences among those who developed DKA episodes and those who did not, and among those who stopped the combination modality.

The findings of our study suggest that although the most physiological modality nowadays is AHCL, until it is available to all, and accepted to be used by all, sometimes “out of the box” solutions for specific challenging patients should be suggested. The combination modality of rapid-acting insulin delivered by pump for boluses in combination with subcutaneously injected long-acting insulin once daily may enable all benefits of a pump use among youth with T1D, without deleteriously affecting glycemic control, and while providing protection from DKA. This treatment strategy is mainly suitable for the pubertal ones, with poorly controlled diabetes. It may also be welcomed by young people living with diabetes who reject constant pump use due to body image or intensive physical activity, but still want the benefit of delivering insulin without an additional subcutaneous injection.