Insulin is the treatment of choice for diabetes care in the hospital. There is some debate regarding the efficacy and safety of once-daily versus twice-daily insulin glargine in the hospital, particularly in the critically ill population.
The purpose of this pilot study was to evaluate the efficacy and safety of insulin glargine administered as a once-daily versus twice-daily regimen in the noncritically ill population.
A retrospective chart review was conducted from 1 June 2020 to 31 May 2021. Inclusion criteria were age ≥18 years and on a regimen of either once-daily or twice-daily insulin glargine for ≥72 hours during the specified time frame. The primary end point was a comparison of the number of days with all blood glucose measurements within the range of 70–180 mg/dL throughout a 24-hour period. Secondary end points included the number of hyperglycemic (>180 mg/dL) and hypoglycemic (<70 mg/dL) events that occurred in each study group.
Group 1 included 101 individuals who received once-daily dosing, and group 2 included 103 individuals who received twice-daily dosing. Baseline characteristics were similar between the groups except for a higher BMI at admission (P = 0.01) and a higher pre-admission A1C (P = 0.02) in group 2. No differences were found for the primary end point (P = 0.5) or for hypoglycemic (P = 0.6) or hyperglycemic (P = 0.7) events.
There were no significant differences in efficacy or safety between once-daily and twice-daily insulin glargine in the noncritically ill population. A larger prospective study could confirm these results.
In the inpatient setting, glycemic management is essential for people with diabetes or stress hyperglycemia because hyperglycemia can lead to longer hospitalizations and more complications. The Standards of Care in Diabetes—2024 of the American Diabetes Association (ADA) recommends insulin as the treatment of choice in the hospital. Because of its pharmacokinetic profile, insulin therapy can be matched with hospital-related factors and adjusted based on drug- and person-related factors (1,2). Various insulin regimens may be used in the hospital setting, although a basal-bolus regimen is preferred (1). For noncritically ill individuals with poor oral intake, the recommended treatment is basal insulin alone or in combination with correctional insulin (1). For noncritically ill individuals who are able to tolerate adequate nutritional intake, the insulin regimen may consist of basal, prandial, and correctional products (e.g., a basal-bolus regimen). Treating hyperglycemia with only correctional insulin is strongly discouraged (1).
Insulin glargine was the first recombinant, long-acting insulin to be produced and is commonly used as a basal insulin in both outpatient and inpatient settings (3). Because of its duration of action of ∼24 hours, insulin glargine is traditionally given as a once-daily dose. In clinical practice, twice-daily regimens may be preferred when an individual’s total daily insulin requirement is >80–90 units/day or when hyperglycemia persists despite titration of the existing insulin regimen (4).
In the hospital setting, most evidence favors twice-daily dosing of insulin glargine for the critically ill population (5). A study including 58 participants in an intensive care unit (ICU) compared the efficacy and safety of once-daily versus twice-daily insulin glargine (5). This study was conducted because of some data suggesting that the actual duration of action of insulin glargine may vary widely, between 10.5 and 29 hours. This study found that a twice-daily regimen provided a significant reduction in the pre-dose hyperglycemia observed before subsequent once-daily doses (5). A case report (6) described a critically ill individual with an intracerebral bleed on a twice-daily insulin glargine regimen to address consistent hyperglycemia that occurred 1 hour after the nightly administration of a once-daily dose of this basal insulin. Once the patient began to receive the twice-daily regimen, the hyperglycemia just after the evening dose resolved and was attributed to insulin glargine’s slow onset of action (6).
This pilot study was conducted because of the limited available data in the noncritically ill population comparing the efficacy and safety of insulin glargine administered in a once-daily versus twice-daily regimen.
Research Design and Methods
This study was a retrospective chart and electronic medical record (EMR) review conducted at Spartanburg Regional Healthcare System (SRHS). This community-based health care system of ∼800 beds serves the community within the upstate region of South Carolina. The study was approved by the SRHS institutional review board. Data were retrieved from the EMR system.
Design and Participants
Participants were from the following hospitals within the system: Spartanburg Medical Center (SMC)–Church Street, Pelham Medical Center, Union Medical Center, Cherokee Medical Center, and SMC–Mary Black. To be included, individuals had to have been hospitalized on non-ICU wards, ≥18 years of age, and treated with insulin glargine for ≥72 hours in either a once-daily or twice-daily regimen between 1 June 2020 and 31 May 2021. Individuals were excluded if they had been positive for coronavirus disease 2019, pregnant, a prisoner, admitted for diabetic ketoacidosis or hyperosmolar hyperglycemic state, or managed on an ICU floor at any time during their hospitalization or if they received steroids or an insulin drip during their hospital stay. Data collected included age, BMI, primary admission diagnosis, pre-admission A1C, history and duration of diabetes, home insulin use, home insulin regimen, length of hospital stay, inpatient daily bolus insulin dose, and nutritional status at the time of any hypoglycemic event.
Primary and Secondary End Points
The ADA recommends a blood glucose target in the hospital setting of 140–180 mg/dL, although this target may be tightened to 110–140 mg/dL for select individuals who can achieve it without hypoglycemia (blood glucose <70 mg/dL). Therefore, a target range of 70–180 mg/dL was selected for this study. The primary end point was the number of days during which all point-of-care (POC) blood glucose measurements were within the target range over a 24-hour period. Secondary end points were the number of hyperglycemic (POC glucose values >180 mg/dL) and hypoglycemic (POC glucose values <70 mg/dL) events within each study group.
Statistical Analysis
This study was considered a pilot study because there had not been a previous study with an SD that analyzed a similar end point in the noncritically ill population. Once data were collected, an SD was identified to determine whether the study had adequate power. Descriptive statistics were calculated for the dependent variable of each group. t Tests or ANOVA were used for continuous data that were found to be normally distributed. Nonparametric tests used were the Fisher exact and Wilcoxon/Kruskal-Wallis rank sum tests for continuous and categorical data, respectively. P values were calculated using a 95% CI, and P <0.05 was considered statistically significant.
Results
Baseline Characteristics
A total of 204 patients were included in this study, with 101 receiving once-daily glargine (group 1) and 103 receiving the twice-daily glargine regimen (group 2). Baseline characteristics were similar between groups except for a significantly higher admission BMI (P = 0.01) and a significantly higher pre-admission A1C (P = 0.02) in group 2. Baseline characteristics are summarized in Table 1.
Baseline Characteristics
| . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Age, years | 63.2 | 63.6 | 0.7742 |
| Male sex | 58 (57.4) | 49 (47.6) | 0.1645 |
| Length of stay, days | 7.1 | 6.4 | 0.0762 |
| Duration of therapy, days | 6.7 | 6.7 | 0.7519 |
| Admission BMI, kg/m2 | 33 | 35.6 | 0.0142* |
| Pre-admission A1C, % | 8.7 | 9.5 | 0.0220* |
| History of diabetes | 97 (97) | 100 (100) | 0.2462 |
| Home insulin use | 89 (89) | 94 (94) | 0.3106 |
| . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Age, years | 63.2 | 63.6 | 0.7742 |
| Male sex | 58 (57.4) | 49 (47.6) | 0.1645 |
| Length of stay, days | 7.1 | 6.4 | 0.0762 |
| Duration of therapy, days | 6.7 | 6.7 | 0.7519 |
| Admission BMI, kg/m2 | 33 | 35.6 | 0.0142* |
| Pre-admission A1C, % | 8.7 | 9.5 | 0.0220* |
| History of diabetes | 97 (97) | 100 (100) | 0.2462 |
| Home insulin use | 89 (89) | 94 (94) | 0.3106 |
Data are mean or n (%).
Statistically significant.
Study Findings
No differences were found between the two groups for the primary end point (P = 0.5) or the secondary end points of hypoglycemic (P = 0.6) and hyperglycemic (P = 0.7) events (Table 2). For exploratory findings, there was no difference between the two groups in the mean inpatient daily bolus dose. As anticipated, there was a significantly higher total dose of insulin glargine with the twice-daily regimen in group 2. Additionally, the mean daily glargine doses were 22 and 45 units for the once-daily and twice-daily regimens, respectively. The proportion of days with all POC glucose measurements within target was 23.3 and 27% for the once-daily and twice-daily regimens, respectively (Table 3).
Primary and Secondary End Points
| Finding . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Number of days all POC glucose measurements were 70–180 mg/dL | 1.6 | 1.8 | 0.4522 |
| Number of hypoglycemic events (glucose <70 mg/dL) | 0.4 | 0.3 | 0.5775 |
| Number of hyperglycemic events (glucose >180 mg/dL) | 6.2 | 5.1 | 0.7424 |
| Finding . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Number of days all POC glucose measurements were 70–180 mg/dL | 1.6 | 1.8 | 0.4522 |
| Number of hypoglycemic events (glucose <70 mg/dL) | 0.4 | 0.3 | 0.5775 |
| Number of hyperglycemic events (glucose >180 mg/dL) | 6.2 | 5.1 | 0.7424 |
Data are means.
Other Exploratory Findings
| Finding . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Inpatient daily bolus dose, units | 13.2 | 15.9 | 0.2181 |
| Total glargine dose, units | 144.8 | 301.7 | <0.0001* |
| Daily glargine dose, units | 21.7 | 45.3 | — |
| Days all POC glucose measurements were 70–180 mg/dL, % | 23.3 | 27 | — |
| Finding . | Group 1 (n = 101) . | Group 2 (n = 103) . | P . |
|---|---|---|---|
| Inpatient daily bolus dose, units | 13.2 | 15.9 | 0.2181 |
| Total glargine dose, units | 144.8 | 301.7 | <0.0001* |
| Daily glargine dose, units | 21.7 | 45.3 | — |
| Days all POC glucose measurements were 70–180 mg/dL, % | 23.3 | 27 | — |
Data are means.
Statistically significant.
Discussion
This study demonstrated that there was no difference in efficacy or safety when insulin glargine was administered in a once-daily versus a twice-daily regimen in the noncritically ill population. Other findings of this study included the calculated mean daily insulin glargine dose in each group. This exploratory finding identified that the dosing of insulin glargine when given as a twice-daily regimen did not meet the threshold of 80–90 units/day for which twice-daily dosing is recommended. Therefore, these individuals potentially could have received insulin glargine in a once-daily regimen and achieved the same glycemic effect. Additionally, the percentage of days during which all POC glucose measurements were within the target range was calculated to identify a potential opportunity for quality improvement within this single health care system. The proportion of hospitalization days with all glucose levels 70–180 mg/dL was <30% in each group.
The results of this pilot study are both similar to and different from those of another study that evaluated insulin glargine twice daily in the critically ill population. Fox et al. (5) found that twice-daily dosing was favored over once-daily dosing of insulin glargine in a small sample size within the ICU (5). Most of these individuals were male and >60 years of age. Baseline characteristics were similar between the two groups, with a median BMI >30 kg/m2 and a mean A1C within 3 months of admission of 7.4% in the once-daily group and 8.7% in the twice-daily group. Although pre-admission A1C was greater in the twice-daily group, this difference was not found to be statistically significant (P = 0.24). The results of that study also demonstrated that there were no significant differences in mean glucose levels (154 and 153 mg/dL for the once-daily and twice-daily groups, respectively). There were also no statistically significant differences in the overall incidences of hyperglycemia (P = 1.00) or hypoglycemia (P = 0.29). However, daily insulin glargine doses were significantly higher in the twice-daily group (58 vs. 45 units, P = 0.04). The pre-dose hyperglycemia rate, which was rate of glucose levels >180 mg/dL within 4 hours before the dose, was also significantly lower in the twice-daily group (0.43 vs. 0.27, P = 0.02). This finding indicated that individuals receiving twice-daily dosing were less likely to have hyperglycemia before receiving the next dose. The overall percentage of subjects who achieved glycemic control was similar between groups (43 and 52% of those receiving insulin glargine once daily and twice daily, respectively. Our pilot study in a noncritically ill population had a higher pre-admission A1C in the twice-daily group, which was found to be statistically significant. Lastly, there were no differences in our noncritically ill population for hyperglycemia and hypoglycemia, which were similar findings to the critically ill population (5).
In a case report involving a 53-year-old man who was hospitalized for a massive intracerebral bleed, the individual had a known history of type 1 diabetes, and the authors proposed that the duration of action of insulin glargine may have been too short for once-daily dosing in that case (6). Throughout the hospital stay, the individual was first transitioned from an insulin drip for treatment of diabetic ketoacidosis to a basal-bolus subcutaneous insulin regimen involving once-daily insulin glargine and correctional insulin lispro. He was then transitioned to a basal-bolus regimen involving 10 units twice-daily insulin glargine given at 9:00 a.m. and 11:00 p.m. along with the correctional insulin lispro. Once the twice-daily regimen was initiated, the 1-hour post-dose POC blood glucose levels were compared and had significantly decreased with the twice-daily dosing regimen (mean glucose 226 ± 37 vs. 132 ± 27 mg/dL, P <0.005). Conclusions were made that hyperglycemia after the once-daily dose arose because of the slow onset of action of insulin glargine, which resulted in a temporary period of insulin deficiency (6). It is difficult to compare a case report of a single individual to our pilot study of 204 patients. The case report highlights the importance of person-centered care in the hospital to improve glycemic control and other diabetes-related outcomes (e.g., length of stay and hypoglycemic episodes).
Although a twice-daily regimen may be required in certain clinical scenarios, the ability to optimize a once-daily regimen for hospitalized individuals can provide benefits for the individuals and clinical staff as well as the health care system as a whole. Once-daily insulin administration can reduce individuals’ anxiety by decreasing the number of injections they receive per day, which may improve their satisfaction and promote adherence for those who are discharged on insulin therapy. Decreasing the frequency of insulin administration can also reduce the workload on nurses and potentially the cost of supplies such as alcohol wipes and needles associated with insulin therapy.
Limitations
There are limitations of this pilot study. First, the study did not include the timing of each hyperglycemic event to directly compare with the two earlier studies in the critically ill population. Also, the study’s retrospective design led to dissimilar baseline characteristics between the two groups, including a higher admission BMI and higher pre-admission A1C in group 2. This study also required retrospective data collection, which could have been affected by inconsistent documentation within the EMR system among various nursing staff members and shifts. Although the study was found to have sufficient power retrospectively and after statistical analysis, its small sample size may have limited the generalizability of its findings. Finally, there are no previous similar studies with which to compare this pilot study.
Conclusion
Insulin glargine given as twice-daily injections did not demonstrate any benefits over a once-daily regimen in the noncritically ill population in this study. Understanding that each person should receive individualized care, it may be feasible to establish criteria for a once-daily regimen and to optimize doses of a basal insulin such as insulin glargine before initiating a twice-daily regimen. This strategy can reduce the number of injections per day and decrease the nursing workload without having a negative impact on efficacy or safety outcomes. A prospective randomized controlled trial would be ideal to confirm the findings of this study and investigate any cost savings that may be associated with once-daily dosing of insulin glargine in the noncritically ill inpatient population.
Duality of Interest
No potential conflicts of interest relevant to this article were reported.
Author Contributions
D.H. collected and analyzed the data. D.H. and A.W. designed the project. J.C. conceived the idea. All of the authors wrote and edited the manuscript. D.H. and J.C. are guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the analysis.
Prior Presentation
The results of this study were presented in abstract form at the American College of Clinical Pharmacy Global Conference on Clinical Pharmacy, San Francisco, CA, 15–18 October 2022.
