Benjamin R. Michalove, PharmD

To examine predetermined characteristics of patients who require increases in basal insulin dose compared with those requiring no increase following conversion from insulin glargine to insulin detemir.

This retrospective chart review of patients converted from insulin glargine to insulin detemir was conducted at a Veterans Affairs Medical Center. 

Characteristics of patients who required an increase in basal insulin dose were compared with patients who did not require an increase after the conversion. The following patient characteristics were evaluated: age, body mass index, and tobacco use, and diagnoses of heart failure, hypertension, hyperthyroidism, and hypothyroidism. 

A total of 330 patients were included in this study, and these individuals were categorized into groups for comparison. Group 1 (n = 73) contained patients who did not require an increase in dose following conversion. Group 2 (n = 116) contained patients who required an increase in dose. The 2 groups (Group 1 vs Group 2) did not significantly differ in any of the characteristics studied (P >.05). The remaining patients (Group N; n = 141) did not meet criteria for Group 1 or Group 2. 

There were no statistically significant differences in the studied characteristics of patients who required an increase in basal insulin dose when compared with those of patients who did not require an increase in dose after conversion. Further studies are needed to discern the factors shared by a subset of patients who require an increase in basal insulin dose following conversion.

Diabetes is a chronic, progressive disease that affects more than 21 million individuals in the United States alone.

 Several landmark trials have demonstrated the clinical benefits of tight glycemic control, which include reducing the incidence and delaying the progression of microvascular complications and macrovascular events, such as myocardial infarction, stroke, and cardiovascular death.

 Of the available glucose-lowering agents, insulin is established as the most effective for achieving maximum glycemic control. In fact, guidelines from both the American Association of Clinical Endocrinologists and the American Diabetes Association recommend insulin as first-line therapy, with or without other antidiabetic medications, for symptomatic patients with a markedly elevated glycated hemoglobin (A1C) value.

 According to the National Diabetes Statistics Report, almost 30% of patients with diagnosed diabetes use insulin therapy in the United States, and most patients with type 2 diabetes (T2D) will eventually require basal insulin to achieve or maintain their therapeutic target.

There were 2 basal insulin analogues marketed in the United States at the time of this study: glargine (Lantus) and detemir (Levemir). Although there are no clinical differences in safety and efficacy between the 2, they are different chemical entities with different mechanisms of action.

 Insulin detemir contains an acylated fatty-acid chain that allows reversible binding with albumin, which provides slow absorption from the injection site and distribution to the target tissues, leading to a dose-dependent onset and duration of action. Insulin glargine forms micro-precipitates on injection, causing a slow release into the bloodstream.

 With these differences in action, it is plausible that the 2 may exhibit different pharmacokinetics and dynamics.

Clinical trials comparing insulin detemir and insulin glargine in T2D have provided conflicting results in terms of dose, duration of action, and/or frequency of administration.

 Studies of the conversion from insulin glargine to insulin detemir report that some patients who are switched from insulin glargine to insulin detemir may require more frequent administration and higher insulin doses; however, these studies have not addressed the potential reasons why this may be the case.

 The preferred formulary basal insulin agent at a Veterans Affairs Medical Center (VAMC) was changed from insulin glargine to insulin detemir in January 2013; subsequently, patients receiving insulin glargine were converted to insulin detemir. A medication utilization evaluation was performed, evaluating the change in basal insulin requirements (units per day) and the change in diabetes control (A1C) for a subset of patients. The insulin requirements and/or the A1C increased for more than 50% of patients after the conversion. These results raised the question of why some patients may experience increases in basal insulin requirements with a loss of, or minimal change in, glycemic control, whereas other patients may not require these dose increases.

Currently, limited data exist on the effects of various patient-specific characteristics on basal insulin dosing, and there are no reports of the effects of characteristics on the conversion between basal insulin analogues. Nevertheless, characteristics that affect insulin dose requirements, insulin absorption, insulin action, insulin resistance, and/or glucose metabolism have been documented.

 The effects of age and body mass index (BMI) on increasing insulin dose requirements have been established. Smoking has been shown to reduce insulin absorption, impair insulin action, and increase insulin resistance; therefore, smoking may have an effect on insulin dose requirements.

 Heart failure (HF) has been associated with increased insulin resistance, and the use of diuretics commonly prescribed for patients with HF have harmful effects on glucose metabolism. Despite this, the effects of HF on insulin dose requirements have not been reported.

 Hypertension (HTN) often coexists with insulin resistance, and antihypertensive drug classes exhibit various effects on glucose metabolism; diagnosis and treatment of HTN may affect insulin dose requirements.

 Thyroid disease has been linked to disorders of carbohydrate metabolism and the development of insulin resistance, and this may also affect insulin dose requirements.

 The primary objective of this study was to evaluate the patient characteristics that may influence the need for increased basal insulin doses when converting from insulin glargine to insulin detemir.

This retrospective study, approved by the local institutional review board, evaluated the electronic health records (EHRs) of patients converted from insulin glargine to insulin detemir on or after January 1, 2013, at a VAMC. Patients were selected randomly, and study eligibility was determined for a total sample size of 330 patients. Patients with T2D who were converted from insulin glargine to detemir were included if both basal insulin analogues were received from VAMC. Patients were excluded from the study if they did not have at least 2 A1C measurements recorded during the preconversion and postconversion periods. Furthermore, patients did not meet eligibility criteria if they had a diagnosis of type 1 diabetes.

Once this patient population was identified, patients’ EHRs were reviewed. Patient data between July 1, 2011, and July 1, 2014, were collected. This allowed adequate time for a patient to have A1C measurements drawn during the preconversion and postconversion periods. A1C measurements on or before the date of conversion were included as preconversion measurements, and A1C measurements after the date of conversion were included as postconversion measurements. In evaluating change in A1C after conversion, investigators averaged the preconversion measurements and the postconversion measurements for comparison. A significant increase in A1C was defined as an increase greater than 0.4. This value was chosen because it was the noninferiority margin recommended by the FDA in phase 3 trials of insulin detemir.

In order to determine the dose of insulin most closely associated with each A1C, investigators recorded the doses of insulin glargine and insulin detemir from the prescription orders in the 90 days prior to each A1C measure. Insulin glargine doses were averaged together to produce 1 preconversion dose, and insulin detemir doses were averaged together to produce 1 postconversion dose for comparison. The change in A1C and insulin dose was used to determine if the patient experienced no significant increase in A1C and no increase in insulin dose, or if they experienced an increase in A1C and/or an increase in insulin dose following conversion from insulin glargine to insulin detemir. Then, patient characteristics were recorded to determine which, if any, patient-specific factors may be associated with an increase in insulin dose requirement following the conversion from insulin glargine to insulin detemir.

 The patients were divided into groups based on change in A1C and change in insulin dose (

). The following patient characteristics were compared between the groups to identify which, if any, may identify a population with a higher likelihood of requiring an increased dose of insulin detemir after conversion from insulin glargine: age, BMI, and tobacco use at the time of conversion, and diagnoses of HF, HTN, hyperthyroidism, and hypothyroidism (

Demographic characteristics on the study sample were computed and reported as mean and standard deviation or percent with attribute (when applicable). A one-way analysis of variance test was applied on the continuous variables (age, weight, height, and BMI) for comparing group averages and a 

 test was used for categorical variables (tobacco use, HTN, HF, hypothyroidism, and hyperthyroidism) to compare proportions. A 

 value of <.05 was considered significant.

A total of 330 patients were included in this study. The results summarized in Table 1 show that the average age of the patients was 69 years (range = 46-98 years). Almost all patients were male (>98%) and more than 90% were Caucasian. The average weight, height, and BMI were 102.6 kg, 177.3 cm, and 32.6 kg/m

, respectively. At the time of the study, 1 of 5 patients used tobacco products. Approximately 94% of the sample had a diagnosis of HTN, with fewer than 9% with documented diagnosis of HF. The percentages of patients with diagnoses of hypothyroidism or hyperthyroidism in our sample were 18.5% and 1.2%, respectively.

Of the 330 patients in the study sample, 22.1% (n = 73) experienced an insulin dose decrease or lack of change, with a nonsignificant change in A1C (<0.4 increase, decrease, or no change) (Group 1). Group 2 (n = 116) patients required an increase in the insulin dose and the A1C value increased or did not change in its value. The 2 groups (Group 1 vs Group 2) did not significantly differ in any of the characteristics studied (

>.05) (Table 2). The remaining patients (Group N; n = 141), did not meet the criteria for Group 1 or Group 2 (Figure). These patients either experienced an insulin dose increase and the A1C value decreased, or the patients experienced no increase in insulin dose and the A1C value increased significantly (>0.4 increase). When comparing all 3 groups (Group 1, Group 2, and Group N), there was no statistically significant difference found among the groups with respect to any of the characteristics studied (

Although there are identified patient-specific factors affecting insulin dosing, there are limited data specific to dosing requirements between basal insulin options. This study attempted to assess if specific patient factors—including age, BMI, tobacco use at the time of conversion, and diagnoses of HF, HTN, hyperthyroidism, and hypothyroidism&mdash;were related to changes in insulin dose requirements between insulin glargine and insulin detemir. The results did not indicate any statistically significant difference among the groups for these patient-specific factors.

Although the variation in the dosing requirements among the patients reviewed may not be explained by the presence or lack of presence of the factors examined, there may be other causes contributing to the dissimilarities. Compliance with the insulin regimen and initiation or discontinuation of concomitant medications could have affected dosing requirements. With limited data on the effects of various patient-specific characteristics on basal insulin dosing, other disease states and unknown patient factors could be causative. Further studies could evaluate compliance, prescribed medications, other disease states, and additional patient characteristics.

Limitations to this retrospective study exist. The patient population studied predominantly included Caucasian males. It is difficult to properly ascertain tobacco use, because this is not always accurately documented. Only a small number of patients had certain documented health conditions, such as HF and hyperthyroidism.

 Within the EHR, however, diagnoses are not always included on the “problem list,” so the number of patients with these conditions could be falsely low. Also, with each insulin dose change, providers do not always update the insulin prescription. This could lead to incorrect insulin doses being associated with an A1C result within the study. Often, the preconversion and postconversion periods were not of equal length. There was no wash-out period when converting from insulin glargine to insulin detemir, so insulin glargine doses prior to conversion may have influenced the first A1C results associated with insulin detemir in the study. Compliance with insulin therapy was also not confirmed and certainly could affect glucose control if adherence was an issue.

Determining specific patient characteristics associated with more frequent administration and higher dose requirements after conversion from basal insulin glargine to detemir could facilitate providers in predicting which patients are more likely to experience these concerns, thus decreasing patient—provider frustration, overall healthcare costs, and the prospect of any negative impact on A1C.

The fact that there were no statistically significant differences in patient characteristics between the groups does not necessarily indicate a lack of causal relationship because the studied characteristics are well documented in the medical literature as impacting insulin pharmacokinetics and dynamics. However, the results reinforce the importance of further studies to discern the correlation between a subset of patients who require an increase in insulin administration and/or dose when converting from insulin glargine to insulin detemir.

 Charles George Veterans Affairs Medical Center (DWD, BG, BRM), Asheville, NC; Campbell University, College of Pharmacy and Health Sciences (AA-A), Buies Creek, NC.

 This material is the result of work supported with resources and the use of facilities at the Charles George Veterans Affairs Medical Center located in Asheville, North Carolina. The contents do not represent the views of the US Department of Veterans Affairs or the US government. 

The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (DWD, BG, AA-A, BRM); acquisition of data (DWD); analysis and interpretation of data (DWD, AA-A); drafting of the manuscript (DWD, BG, AA-A, BRM); critical revision of the manuscript for important intellectual content (DWD, BG, AA-A, BRM); statistical analysis (AA-A); obtaining funding (DWD, BG, BRM); administrative, technical, or logistic support (DWD, BG, BRM); and supervision (DWD, BG, BRM). 

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Articles

The characteristics of patients who require increases in their basal insulin dose were compared with those requiring no increase following conversion between basal insulin analogues.