For patients not in DKA requiring an insulin drip for persistent hyperglycemia inpatient, what evidence supports overlapping long-acting insulin during drip transition.

Comment by InpharmD Researcher

Evidence on the safety and efficacy of overlapping long-acting basal insulin during transition from intravenous (IV) insulin in non-diabetic ketoacidosis (DKA) inpatients remains limited. Societal guidelines recommend initiating basal insulin 1-4 hours before discontinuing IV insulin, with dosing generally derived from the patient’s recent IV insulin exposure; however, available guidance does not distinguish between DKA and other hyperglycemic states. Observational data similarly suggest that a 1-4 hour overlap of long-acting or intermediate-acting basal insulin can mitigate rebound hyperglycemia, maintain glycemic control, and in some cases reduce length of stay without increasing hypoglycemia risk. Despite the lack of high-quality trials, available evidence supports a brief basal overlap as a reasonable and safe strategy for persistent inpatient hyperglycemia.

Background

A 2024 consensus report from the American Diabetes Association (ADA) on hyperglycemic crises in adults with diabetes states that during the transition to maintenance insulin therapy in the hospital, to prevent recurrence of hyperglycemia or ketoacidosis, it is important to allow an overlap of 1-2 hours between the administration of subcutaneous insulin and the discontinuation of intravenous insulin, with basal insulin initiated at least 1-2 hours before stopping the IV infusion. While the report refers to basal insulin and notes that first-generation basal analogues and Neutral Protamine Hagedorn (NPH) insulin are frequently administered once daily, it does not explicitly mention long-acting insulin, though basal analogues are implied. Of note, this guidance applies to both diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS), and the recommended transition techniques do not appear to differentiate between these conditions. [1]

According to the 2014 Society of Critical Care Medicine (SCCM) guidelines for the use of an insulin infusion in the management of hyperglycemia in critically ill patients, several models have been proposed for transitioning from intravenous to subcutaneous insulin; however, the supporting evidence is of low quality. Most transition models include basal, nutritional (prandial), and correction insulin components, with basal insulin, either long-acting every 24 hours (e.g., glargine) or intermediate-acting every 6-12 hours (e.g., NPH), recommended to be administered at least 2-4 hours before stopping the infusion to prevent rebound hyperglycemia. Total daily basal doses are often calculated from the preceding IV insulin requirements, with many authors reducing the dose to 80% of the estimated total daily dose to improve glucose control, although 60-70% has also been used successfully. When overlap is not feasible, a simultaneous injection of rapid-acting insulin (approximately 10% of the basal dose) may be given with the basal insulin at the time the infusion is stopped. The guidance does not specifically address DKA, suggesting that these transition principles may be applied to non-DKA hyperglycemia in critically ill patients. [2]

A 2012 article discusses insulin therapy for the management of hyperglycemia in hospitalized patients. At the time of this publication, the authors noted that subcutaneous insulin had not been formally studied in ICU patients and should generally be avoided in critically ill patients, particularly during hypotension or shock, because factors related to critical illness and the perioperative period can alter insulin absorption and increase the risk of overlapping doses, timing errors, and unexpected hypoglycemia. The article emphasizes that all patients with type 1 diabetes and most patients with type 2 diabetes receiving continuous IV insulin require transition to a subcutaneous insulin regimen. Several models for this transition have been proposed, generally involving extrapolating the 24-hour insulin requirement from the preceding 6–8 hours of IV insulin or using weight-based calculations, while considering nutritional status, concurrent medications, and ongoing glucose monitoring. Safe transition strategies typically assign approximately 80% of the total daily insulin dose into basal and prandial components aligned with the patient’s nutrition plan, with an overlap of 1–2 hours between IV discontinuation and subcutaneous basal insulin administration to prevent recurrent hyperglycemia. Basal insulin may be given as a single long-acting daily dose (e.g., glargine or detemir) or as two intermediate-acting NPH doses every 12 hours, and short- or rapid-acting insulin can be added as needed depending on caloric intake and glucose levels. For patients with mild stress hyperglycemia and low IV insulin requirements (≤1–2 U/h) at the time of transition, scheduled subcutaneous insulin may not be necessary, and correction doses alone may suffice. [3]

References:

[1] Umpierrez GE, Davis GM, ElSayed NA, et al. Hyperglycaemic crises in adults with diabetes: a consensus report. Diabetologia. 2024;67(8):1455-1479. doi:10.1007/s00125-024-06183-8
[2] Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):3251-3276. doi:10.1097/CCM.0b013e3182653269
[3] McDonnell ME, Umpierrez GE. Insulin therapy for the management of hyperglycemia in hospitalized patients. Endocrinol Metab Clin North Am. 2012;41(1):175-201. doi:10.1016/j.ecl.2012.01.001

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

For patients not in DKA requiring an insulin drip for persistent hyperglycemia inpatient, what evidence supports overlapping long-acting insulin during drip transition.

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-5 for your response.


Transition From Intravenous to Subcutaneous Insulin: Effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome
Design

Prospective observational study

N= 142

Objective To assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and to identify predictors of transition outcome
Study Groups All patients (n= 142)
Inclusion Criteria Patients consecutively admitted to the Ospedale di Desio ICCU from May 2006 to May 2008 for suspected ACS and known diabetes, or with BG >200 mg/dL
Exclusion Criteria BG remained within the target interval (100–139) in the last 24 h with <0.5 units/h of insulin, thus with estimated daily insulin needs <12 units
Methods

Patients received 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial. BG was measured in venous blood every 1–2 h during intravenous insulin infusion and in capillary blood before and 2 h after each meal during subcutaneous insulin using a bedside glucometer.

Notably, conversion to subcutaneous insulin began on the first day's evening meal, giving the first dose of insulin glargine 2 hours before dinner.

Duration May 2006 to May 2008
Outcome Measures

Primary: Percentage of BG in the range of 100–140 mg/dL before meals and 100–180 mg/dL after meals on the first day after transition 

Secondary: Hypoglycemia

Baseline Characteristics Characteristic All patients (n= 142)
Age, years (mean ± SD) 69.8 ± 10.1
Male 93 (65.4%)
History of diabetes before hospital admission 135 (95.1%)
Type 2 diabetes 130 (91.6%)
BMI, kg/m² (mean ± SD) 28.2 ± 4.4
Glycated hemoglobin, % (mean ± SD) 7.7 ± 1.6
BG at hospital admission, mg/dL (mean ± SD) 248.1 ± 99.6
Results Outcome Percentage
BG within 100-140 mg/dL before meals on first day 38.8%
BG within 100-180 mg/dL after meals on first day 51.1%
Hypoglycemia on first day 7.7%
Hypoglycemia on second day 14.8%
Hypoglycemia on third day 14.1%
Adverse Events Pre- or postprandial hypoglycemia (BG <70 mg/dL) occurred in 11 patients (7.7%) on the first day and in 38 patients (26.8%) on the first 3 days after transition
Study Author Conclusions The study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed
Critique

The study provides valuable insights into the transition process from intravenous to subcutaneous insulin in ACS patients, demonstrating effectiveness and safety. However, the study's applicability may be limited to similar settings and patient populations, as it primarily involves patients with known diabetes and ACS. The observational design may also limit the ability to establish causality.

 

References:

Avanzini F, Marelli G, Donzelli W, et al. Transition from intravenous to subcutaneous insulin: effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome. Diabetes Care. 2011;34(7):1445-1450. doi:10.2337/dc10-2023

 

Effect of the Concomitant Use of Subcutaneous Basal Insulin and Intravenous Insulin Infusion in the Treatment of Severe Hyperglycemic Patients
Design

Retrospective observational study

N= 165

Objective To evaluate the incidence of rebound hyperglycemia during the transition period according to the early administration of SC basal insulin with CIII in patients with severe hyperglycemia
Study Groups

Early basal insulin group (n= 86)

Delayed basal insulin group (n= 79)

Inclusion Criteria Subjects aged >18 years with severe hyperglycemia, admitted to SNUBH and received CIII between January 1, 2018 and January 31, 2021
Exclusion Criteria Discharged or transferred within 24 hours of CIII discontinuation, had other indications for insulin therapy within 48 hours of CIII discontinuation, CIII not changed to MSII regimen, CIII discontinued with blood glucose >250 mg/dL, dextrose fluid infusion continued during MSII
Methods

Following administration of an initial intravenous (IV) dose of a rapid-acting insulin analog at 0.1 units/kg, continuous IV insulin infusion (CIII) was initiated, with the infusion rate controlled according to a predefined algorithm. Once CIII was started, it was recommended to begin once-daily subcutaneous (SC) long-acting basal insulin at a dose of 0.25 units/kg, using agents such as Lantus, Levemir, or Tresiba. The study subjects were divided into two groups based on the timing of basal insulin initiation. The early basal insulin group included patients who received their first SC basal insulin within 24 hours of CIII initiation and at least 4 hours before discontinuing CIII. Patients who did not meet these criteria were classified into the delayed basal insulin group. In both groups, if a patient’s blood glucose level fell below 250 mg/dL, intravenous fluids containing 5% or 10% dextrose were administered to prevent hypoglycemia. When patients were eating normally and blood glucose levels were stable, multiple subcutaneous insulin injections (MSII) were initiated. If long-acting basal insulin had not yet been started, MSII was recommended to overlap with CIII for 2 hours. 

Duration January 1, 2018 to January 31, 2021
Outcome Measures

Primary: Incidence of rebound hyperglycemia

Secondary: Length of hospital stay and incidence of hypoglycemia

Baseline Characteristics   Early basal insulin group (n= 86)* Delayed basal insulin group (n= 79)*
Age, years 59.3 ± 21.0 61.6 ± 18.6
Female 29 (33.7%) 31 (39.2%)
BMI, kg/m2 24.0 ± 5.8 23.0 ± 4.6
Previous DM treatment - None 36 (41.9%) 26 (32.9%)

Classification of severe hyperglycemia

DKA

HHS

HHS with ketoacidosis

Non-DKA or HHS

 

20 (23.3%)

17 (19.8%) 

32 (37.2%) 

17 (19.8%) 

 

21 (26.6%)

15 (19.0%)

18 (22.8%)

25 (31.6%)

Current steroid use

8 (9.3%) 18 (23.1%)

HbA1c, %

11.3 ± 2.5  10.6 ± 2.9

*Baseline values are before propensity score matching

BMI, body mass index; DM, diabetes mellitus; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; HbA1c, glycated hemoglobin

Results  

Early basal insulin group (n= 86)

Delayed basal insulin group (n= 79) p-value
Rebound hyperglycemia incidence 54.7% 86.1% <0.001
Length of hospital stay, days 8.5 9.6 0.027
Hypoglycemia incidence 5.8% 5.1% 1.00
Adverse Events

Hypoglycemia incidence did not differ significantly between the early and delayed basal insulin groups (5.8% vs. 5.1%).

Study Author Conclusions Early co-administration of basal insulin with CIII prevents rebound hyperglycemia and shortens hospital stay without increasing hypoglycemic events in patients with severe hyperglycemia.
Critique

The study provides valuable insights into the benefits of early basal insulin administration in preventing rebound hyperglycemia and potentially reducing hospital length of stay. However, its retrospective design and the possibility of selection bias, even with the use of propensity score matching, may limit the generalizability of the findings. Additionally, although the study included classifications of severe hyperglycemia beyond DKA, patients with DKA were still included, which may confound the interpretation of outcomes specific to non-DKA hyperglycemia.

References:

Lim Y, Ohn JH, Jeong J, et al. Effect of the Concomitant Use of Subcutaneous Basal Insulin and Intravenous Insulin Infusion in the Treatment of Severe Hyperglycemic Patients. Endocrinol Metab (Seoul). 2022;37(3):444-454. doi:10.3803/EnM.2021.1341

 

Development of a pharmacist-managed protocol for the transition from intravenous to subcutaneous insulin in critically ill adults
Design

Single-center, retrospective, observational study

N= 40

Objective To evaluate the efficacy and safety of a pharmacist-managed protocol for transitioning critically ill patients from intravenous (IV) to subcutaneous insulin
Study Groups All patients (n= 40)
Inclusion Criteria Patients admitted to the medical or surgical/trauma intensive care unit who received a continuous infusion of IV insulin from January 2019 to April 2021
Exclusion Criteria Patients less than 18 years old, pregnant, incarcerated, or received IV insulin for diabetic ketoacidosis, hyperglycemic hyperosmolar state, calcium channel blocker or β-blocker overdose, or hypertriglyceridemia
Methods

Patients were transitioned from IV to subcutaneous insulin using a pharmacist-managed protocol. Under the protocol, pharmacists calculated the initial basal subcutaneous insulin dose based on the patient’s recent IV insulin requirements. Specifically, the 24-hour IV insulin requirement was determined by averaging the insulin infusion rate over the final 6 hours of stability and multiplying that value by 24. Pharmacists then initiated basal insulin at approximately 50% to 70% of that calculated 24-hour IV insulin dose, consistent with institutional standards and prior studies. The IV insulin target range during infusion was 70–150 mg/dL, in alignment with SCCM guideline recommendations.

Duration January 2019 to April 2021
Outcome Measures

Primary: Percentage of blood glucose (BG) concentrations within the target range of 70 to 150 mg/dL within 48 hours of transition

Secondary: Percentage of BG concentrations within goal range at 0 to 12 hours and 12 to 24 hours, incidence of hypo- and hyperglycemia, percentage of patients requiring dose adjustments after transition

Baseline Characteristics   All patients (n= 40)
Age, years 63 ± 11
Male 21 (53%)
BMI, kg/m2 30.4 ± 8.1
Diabetes mellitus 28 (70%)
HbA1c, (IQR), % 7.6 (7.2-9.4)

Admitting team: MICU

24 (60%)
Abbreviation: BMI, body mass index; HbA1c, glycosylated hemoglobin; IQR, interquartile range; MICU, medical intensive care unit.
Results   All patients (n= 40)
BG in target range at 12 hours 53%
BG in target range at 24 hours 40%
BG in target range at 48 hours 47%
Hypoglycemia incidence 1.0%
Severe hypoglycemia incidence 0%
Hyperglycemia incidence 28%
Severe hyperglycemia incidence 27%
Patients requiring dose adjustments within 48 hours of transition  52%
Adverse Events Low rate of hypoglycemia (1.0%) and no severe hypoglycemia. Hyperglycemia reported for 28% of BG concentrations, severe hyperglycemia for 27%.
Study Author Conclusions Pharmacists can effectively and safely transition critically ill patients from IV to subcutaneous insulin utilizing a standardized protocol.
Critique The study was limited by its single-center, retrospective design and lack of a comparator group. The protocol demonstrated effective glycemic control with low hypoglycemia rates, but higher than expected hyperglycemia rates may have been influenced by the COVID-19 pandemic and associated challenges in patient management.
References:

Gerhardt JM, Dine SA, Foster DR, et al. Development of a pharmacist-managed protocol for the transition from intravenous to subcutaneous insulin in critically ill adults. Am J Health Syst Pharm. 2022;79(Suppl 3):S86-S93. doi:10.1093/ajhp/zxac141

 

Safety and efficacy of transitioning from intravenous to subcutaneous insulin in critically ill patients
Design

Single-center, retrospective cohort study

N= 200

Objective

To describe the real-world practice during insulin transition from IV to SC in intensive care unit (ICU) patients

Study Groups

Basal insulin-containing regimen (n= 130)

Correctional insulin-based regimen (n= 68)

Scheduled regular insulin regimen (n= 2)

Inclusion Criteria Adult ICU patients transitioned to a SC insulin regimen after at least 6 hours on IV insulin infusion
Exclusion Criteria Patients admitted to cardiac surgery ICU or obstetrician-gynecologist unit, patients <18 years, diagnosis of hyperosmolar hyperglycemia syndrome or diabetic ketoacidosis
Methods

The Brigham and Women’s Hospital (BWH) IV-to-subcutaneous insulin transition protocol estimated total daily insulin needs by averaging the last 6 hours of IV insulin, extrapolating to 24 hours, and multiplying by 0.6 to adjust for reduced insulin requirements. The resulting total daily dose was then divided evenly into basal (long-acting) and nutritional (meal) insulin, with additional correctional insulin as needed. Blood glucose was targeted between 100–180 mg/dL, and hourly monitoring was required while on IV insulin. Patients were classified by transition regimen-scheduled regular insulin, basal-containing (NPH or glargine), or correctional-only insulin.

Duration November 1, 2017, to November 1, 2018
Outcome Measures

Transition percentage, dysglycemic events during insulin transition

Baseline Characteristics   All patients (N=200) 
Male 143 (71.5%)
Age, year 61 ± 14.5
Body Mass Index, kg/m2 30.3 ± 8.6
Diagnosis of diabetes 147 (73.4%)
HbA1C 7.34 ± 1.4
Septic shock 75 (41%)
Traumatic brain injury 9 (4.5%)
Hemorrhagic or ischemic stroke 54 (27%)
Medical ICU 88 (44%)
Surgical and trauma ICU 65 (32.5%)
Neurology/neurosurgery ICU 44 (22%)
Burn ICU 3 (1.5%)
Renal impairment 105 (52.5%)
Liver impairment 19 (9.5%)
Enteral nutrition 97 (48%)
Parenteral nutrition 13 (6.5%)
Patients on corticosteroids 76 (38%)
Blood glucose upon ICU admission, mg/dL (IQR) 209 (140–295)
Results   Prior to insulin transition After insulin transition
Moderate hypoglycemic events 1% 0.4%
Severe hypoglycemic events 0.2% 0%
Hyperglycemic events 17.6% 54.2%

The median transition percentage used in the 130 patients that received basal-containing insulin regimen was 45% (IQR 28–69), with a median overlap of 2 (IQR 1-3) hours between IV and SC insulin.

Before transitioning from IV to SC insulin, moderate hypoglycemia occurred in 1% of glucose assessments compared to 0.4% after transition (p= 0.12), and no significant difference was observed in severe hypoglycemia (0.2% vs 0%, p= 0.11). However, hyperglycemia significantly increased following transition, from 17.6% to 54.2% of glucose assessments (p< 0.05). These results indicate that while hypoglycemia did not worsen, maintaining glycemic control post-transition was more challenging, with a marked rise in hyperglycemia events.

Adverse Events

Higher incidence of hyperglycemia after transition (54.2% vs 17.6% prior). Lower incidence of moderate hypoglycemia after transition (0.4% vs 1% prior). No severe hypoglycemic events after transition.

Study Author Conclusions

Patients were converted to SC therapy using a lower transition percentage than previously described. More data are needed to optimize the transition process in critically ill patients.

Critique

The study provides valuable real-world data on insulin transition practices in critically ill patients, highlighting variability in transition percentages and outcomes. However, the retrospective design and single-center setting may limit generalizability. The study did not use advanced analytical techniques to assess risk factors, and the number of blood glucose assessments before and after transition might have affected outcomes.

References:

Alshaya AI, DeGrado JR, Lupi KE, Szumita PM. Safety and efficacy of transitioning from intravenous to subcutaneous insulin in critically ill patients. Int J Clin Pharm. 2022;44(1):146-152. doi:10.1007/s11096-021-01325-z

Subcutaneous Administration of Glargine to Diabetic Patients Receiving Insulin Infusion Prevents Rebound Hyperglycemia
Design

Prospective randomized study

N= 61

Objective To hypothesize that initiation of a long-acting insulin therapy concurrently with iv insulin infusion would decrease the rate of rebound hyperglycemia after discontinuation of the insulin infusion
Study Groups

Control group (n= 31)

Intervention group (n= 30)

Inclusion Criteria Hospitalized patients with known type 1 or type 2 diabetes receiving iv insulin infusion
Exclusion Criteria Patients with newly diagnosed hyperglycemia, critical illness, and pregnant women
Methods Subjects in the intervention group received daily injections of glargine sc (0.25 U/kg body weight) starting within 12 h of initiation of iv insulin infusion. Capillary blood glucose measurements were obtained up to 12 h after discontinuation of insulin infusion. Rebound hyperglycemia was defined as a blood glucose level greater than 180 mg/dl. 
Duration January 2011 to October 2011
Outcome Measures Rates of rebound hyperglycemia between the control and intervention groups after iv insulin infusion is discontinued
Baseline Characteristics   Control (n= 31) Intervention (n= 30)
Male/Female 20/11 18/12
Caucasian/Hispanic/African-American 15/10/6 17/6/7
Age, yr 43.4 ± 15.4 42.7 ± 15.5
Weight, kg 81.0 ± 23.8 76.2 ± 16.5
HbA1c 10.1 ± 2.7 9.7 ± 2.7
Type 1/type 2 15/16 17/13
Results   Control (n= 31) Intervention (n= 30) p-value
Rebound hyperglycemia 93.5% 33.3% <0.001
Adverse Events There were three hypoglycemic measurements in two control subjects (68, 62, and 58 mg/dl) and none in the intervention group. 
Study Author Conclusions Once-daily sc insulin glargine administered during iv insulin infusion is a safe method for preventing future rebound hyperglycemia, without increased risk of hypoglycemia. 
Critique The study demonstrates a significant reduction in rebound hyperglycemia with the use of glargine, but the relatively small sample size and mixed cohort of medical and surgical patients may limit the generalizability of the findings. Additionally, the primary care teams were not blinded, which could have influenced the routine care decisions. 
References:

Hsia E, Seggelke S, Gibbs J, et al. Subcutaneous administration of glargine to diabetic patients receiving insulin infusion prevents rebound hyperglycemia. J Clin Endocrinol Metab. 2012;97(9):3132-3137. doi:10.1210/jc.2012-1244