Subcutaneous Rapid-Acting Insulin Analogs for Diabetic Ketoacidosis

Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, GonzalezPadilla DA. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. Cochrane Database of Syst Rev. 2016;Issue 1. Art. No.: CD011281.

Study Population: 201 participants enrolled in five randomized controlled trials that compared continuous intravenous regular insulin with subcutaneous rapid-acting insulin analogs

Time to resolution of ketoacidosis, episodes of hypoglycemia, and all-cause mortality

Hypoglycemia

Diabetic ketoacidosis (DKA), characterized by hyperglycemia, metabolic acidosis, and ketosis, is a serious complication of diabetes mellitus. Treatment focuses on fluid restoration, correction of hyperglycemia, and inhibition of ketogenesis. Insulin is considered a fundamental component of DKA treatment as it promotes the peripheral tissues’ utilization of glucose in peripheral tissues by reducing hepatic gluconeogenesis and suppressing ketogenesis.1

Early studies of DKA showed no difference in outcomes with regular insulin administered intravenously, intramuscularly, or subcutaneously. However, based on a preference for rapid onset of effects,2 historically DKA has been treated with continuous intravenous regular insulin in the emergency department or in the intensive care unit (ICU). In the last two decades, newly developed insulin analogs such as lispro and aspart have demonstrated rapid onset of effects in patients with DKA,3 suggesting these analogs given subcutaneously may attain effects commensurate with those of intravenous regular insulin for DKA.

The systematic review discussed here included 5 trials (201subjects in total) that compared subcutaneous rapid-acting insulin analogs with standard intravenous infusion of regular insulin in patients with DKA.4 The meta-analysis did not find any statistically significant difference between groups regarding the study primary endpoints of time to resolution of DKA, episodes of hypoglycemia, and all-cause mortality.4 Time to resolution of DKA was defined as time to reach blood glucose levels < 200 mg/dL and two of the following criteria: a serum bicarbonate level ≥ 15 mEq/L, a venous pH >7.3, and a calculated anion gap ≤12 mEq/L. Hypoglycemia was defined as a plasma glucose less than ≤70 mg/dL (3.9 mmol/L) or according to authors’ definition. Although other adverse events were mentioned as secondary outcomes in 2 trials, no events other than hypoglycemia were reported.

The meta-analysis also analyzed secondary outcomes such as length of hospital stay and costs. Three trials including 90 adult patients compared subcutaneous insulin lispro to intravenous regular insulin and found no difference in hospital length of stay.5^, 6^, 7 One study of 40 adults reported hospital costs were significantly lower in the non-critical care setting with subcutaneous lispro.7

The authors of the systematic review rated the quality of evidence for the primary endpoints as mostly low or very low. Other limitations included poor definitions of outcomes, and small numbers of patients and eligible trials. All-cause mortality did not show any significant difference between treatment groups as no deaths were reported. Regarding potential harms, the trials only measured the risk of hypoglycemia and no other harm endpoints were reported.

The clinical implications for resource allocation and medical costs favor subcutaneous insulin as a treatment over continuous infusion of regular insulin for mild to moderate DKA. A retrospective comparison of DKA admissions to the ICU and to step-down units in two academic hospitals in Canada, reported that patients managed in step-down units incurred approximately one-third the cost of an ICU admission.8 The current admission disposition and treatment algorithms are largely institution dependent. However, in the context of increasing demand for limited ICU beds, similar outcomes comparing subcutaneous versus intravenous insulin, and the potential for healthcare cost savings, consideration of subcutaneous rapid insulin analogues as a replacement for intravenous insulin seems logical.9

Enthusiasm for treatment of DKA with subcutaneous should be tempered with caution. Patients with severe DKA and the elderly patients were not included in this review. The applicability in children must also be carefully evaluated since just one study enrolled pediatric patients.10 However, since the publication of the Cochrane review, Razavi et al reported on the use of subcutaneous aspart in 50 pediatric patients with mild-to-moderate DKA and noted decreased time to hospital discharge in the subcutaneous group without change in mortality or adverse events.11

In summary, the use of continuous intravenous regular insulin compared to subcutaneous insulin rapid-acting analogs did not offer increased clinical benefits for patients admitted with mild to moderate DKA. The data appears to be supportive of using this treatment option particularly in non-ICU settings. However, the existing data are severely limited by the small number of trials and small sample sizes, as well as the low quality. Further multi-centered randomized controlled trials detailing patient outcomes, patient satisfaction, and economic end-points are needed. Given the potential benefits in light of significant data limitations, we have assigned a color recommendation of yellow (Unclear If Benefits) to this intervention.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

December 1, 2020