Insulin use and persistence in patients with type 2 diabetes adding mealtime insulin to a basal regimen: a retrospective database analysis

For many patients with type 2 diabetes, initiation of insulin therapy marks the transition of their diabetes condition into a more severe disease state with the potential for more complications. The goal of type 2 diabetes treatment is to maintain a glycosylated hemoglobin (HbA1c) of < 7%, a goal that has been made easier through advances in insulin types and delivery options [1]. However, significant barriers still remain in physicians' and patients' minds regarding insulin use. The Diabetes Control and Complications Trial showed that patients treated with intensive insulin therapy demonstrated a 3-fold increased risk of a severe hypoglycemia event, a finding that physicians are aware of, according to Meece [2]. This awareness can therefore be a factor in clinical inertia for intensifying insulin therapy when patients are no longer controlled with basal insulin [3, 4]. Patient fears regarding possible adverse health consequences associated with intensifying insulin therapy, such as weight gain or hypoglycemia, also factor into adherence to a treatment regimen including mealtime insulin. For most patients, the addition of mealtime insulin also requires insulin administration outside the home, which may have significant lifestyle implications due to public insulin use and inconveniences associated with carrying and storing insulin. Persistence with insulin is often low [5]; 16% to 49% of patients are persistent at 6 to 12 months [5‐8]. Research suggests that medication regimen complexity [7] and higher frequency dosing schedules [9, 10] are barriers to taking insulin. Thus, several treatment-related factors may be significant barriers to successful long-term treatment for some patients.

The primary objective of this study was to describe insulin use among patients adding mealtime insulin to their basal insulin regimen. The secondary objective of this study was to describe persistence to mealtime insulin and determine risk factors for poor persistence with insulin therapy. This study employed a retrospective approach using administrative claims data.

Two Thomson Reuters MarketScan^® research databases were used in this study: the Commercial Claims and Encounters (Commercial) database and the Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) Database. The Commercial database contains the inpatient, outpatient, emergency room, and outpatient prescription drug experience of several million individuals and their dependents in the United States. The overall database includes individuals from over 100 self-insured large employers and health plans. The Medicare Supplemental database contains the healthcare experience of individuals with Medicare supplemental insurance paid for by employers. The methods used in this current study were employed in a similar analysis of insulin naïve patients with type 2 diabetes using the same datasource and study design [11].

A total of 294,769 patients who had 1 or more mealtime insulin claim were identified during the study period. Of this total, 66,805 (22%) patients had a type 2 diabetes diagnosis and continuous enrollment. Requiring 2 claims of basal insulin in the pre-period brought the sample to 19,668. Evidence of type I diabetes caused 13,184 patients to be excluded. An additional 27 patients were excluded for a diagnosis of gestational diabetes or for using inhaled insulin or an insulin pump. This left a total of 6,457 patients on stable basal insulin who initiated a mealtime insulin regimen. Seven hundred forty-eight (approximately 12%) of those patients were excluded from further analysis because they had a claim for an insulin mixture in the post-index period. Of the remaining 5,709 patients, 957 (14.8%) had a single mealtime claim, leaving 4,752 as the final sample size of patients with 2 or more mealtime insulin claims in the post-index period.

Table 2 contains the insulin use characteristics of the study sample. The average time between refills over 12 months was 94.5 days (median: 75.5 days). The majority of the sample (80.9%) had a 90-day gap in the 1-year following initiation of mealtime insulin. The mean time to the start of the 90-day gap was 67.6 days, and the time between the start of the 90-day gap and the next claim was 160.0 days. The majority of patients (86.6%) with a 90-day gap had a claim following the gap. Persistence was 40.7% at 3 months, 30.2% at 6 months, and 19.1% at 12 months using measure 1. Persistence was 74.3% at 3 months, 55.3% at 6 months, and 42.2% at 12 months using measure 2.

In terms of demographics, there were several statistically significant differences between persistent and non-persistent patients; however, several of these differences were not of practical importance. For example, persistent patients were statistically but not substantively younger than non-persistent patients (measure 1: 58.6 versus 60.7, p < 0.0001; measure 2: 59.7 versus 60.8 years, p = 0.0043). There were also numerous statistically significant differences between persistent and non-persistent patients in terms of clinical characteristics. Table 3 contains comparisons of demographic and clinical characteristics stratified by persistence status. The mean Deyo Charlson Comorbidity Index score was lower among persistent patients than non-persistent patients (measure 1: 2.05 versus 2.22, p = 0.015; measure 2: 2.10 versus 2.25, p = 0.004). Persistent patients had lower counts of concomitant diabetes medication classes than non-persistent patients (measure 1: 0.86 versus 1.05 classes, p < 0.0001; measure 2: 0.94 versus 1.07 classes, p < 0.0001). Persistent patients were also less likely than non-persistent patients to have diabetes complications (measure 1: 28.5% versus 32.6%, p = 0.017; measure 2: 29.9% versus 33.2%, p = 0.014), macrovascular complications (measure 1: 48.4% versus 50.7%, p = 0.215; measure 2: 48.5% versus 51.6%, p = 0.037), and mental health disorders (measure 1: 5.6% versus 7.4%, p = 0.056; measure 2: 6.2% versus 7.7%, p = 0.040).

Persistent patients were less likely than non-persistent patients to use human insulin at index (36.9% versus 42.3%, p < 0.0001) as defined by measure 2. As expected (by definition of persistence), the number of claims and quantity per day was higher among persistent patients, and time between insulin claims was lower among persistent patients, compared to non-persistent patients. The mean total cost of claims was higher among persistent patients than non-persistent patients (measure 1: $6,122.81 versus $5,663.12, p = 0.009; measure 2: $6,220.88 versus $5,407.54, p < 0.0001) while the average copayment per insulin claim was lower (measure 1: $15.68 versus $18.41, p = 0.007; measure 2: $16.63 versus $18.81, p = 0.007).

The majority of patients initiating mealtime insulin had a 90-day gap in mealtime insulin claims (81%) during the year following their first mealtime insulin claim. According to Sikka and colleagues, patients filling claims following an allowable gap are still considered non-persistent [14]. However, the presence of a 90-day gap is not a measure of complete discontinuation; 87% of patients with a 90-day gap had a mealtime insulin claim following the gap. Of the 3,843 patients with a 90-day claim gap, nearly half (46.2%) had a gap immediately following their index claim. Using a 90-day gap to define insulin persistence increases the likelihood of falsely classifying persistent patients as non-persistent. According to measure 2, which is more lenient and allows for sizeable gaps between the required number of insulin claims, less than half of patients (42%) were persistent at 12 months.

A significant number of patients who met the study inclusion and exclusion criteria (17%) were excluded because they only filled their index mealtime insulin claim. A single mealtime insulin claim may indicate a response to an acute hyperglycemic event and not represent a true intensification of diabetes management. Further investigation of these patients and their reasons for early discontinuation is warranted.

Several factors could be related to the findings regarding insulin type (analog versus human) and delivery (pen versus vial/syringe). Previous research has found that a dislike of injections is related to discontinuing insulin use [8], which might imply that insulin pens may have better persistence than vial/syringe due to the somewhat different nature of the injection. However, this study failed to find a statistically significant relationship between insulin pen use and persistence, similar to the findings of Pawaskar and colleague [15]. This finding may be partly due to the availability of products and the study timeframe. At the same time, the greater dosing flexibility may have contributed to the consistent association between analog insulin and increased persistence. This current analysis could not, however, control for provider-related characteristics or preferences that may be related to insulin persistence and the use of human versus analog or pen versus vial/syringe insulin.

The finding that higher counts of concomitant diabetes medications were positively associated with insulin persistence is inconsistent with existing literature [10]. This association could be due, in part, to the fact that the use of additional classes of OAD agents are a result of healthcare utilization and monitoring. It is also possible that collinearity between the count of OAD classes and diabetes complications is interfering with the multivariate models. This may explain the change in direction from the univariate to the multivariate results.

Caution should be used when interpreting the results of persistency to insulin therapy. There is no validated measure available to measure insulin adherence and persistence. The presence of a claim gap (measure 1) is a commonly used measure for persistency [16]. The original formulation of measure 2 incorporated the current number of claims structure and a requirement of 0.10 mL index insulin per day, on average. Descriptive analyses of the average quantity of insulin per day did not provide a clear, clinically relevant cut-off that did not appear arbitrary. Descriptive analysis also indicated that the number of claims requirement, as opposed to the insulin quantity per day, largely determined persistence status. Both of these reasons support excluding insulin quantity per day from persistence determination.

By either measure, non-persistence indicates a significant break in a patient's use of mealtime insulin that is reflected both in time off of therapy and in average daily dose of insulin. Non-persistent patients had an average total daily insulin dose of 0.30 mL (non-persistent by measure 1) and 0.27 mL (non-persistent by measure 2), which included average daily mealtime insulin dose per day of 0.13 mL and 0.10 mL, respectively. While the recommended quantity of mealtime insulin per day differs by patient, these levels are significantly lower than would be expected in a group of patients with adequately managed type 2 diabetes using mealtime insulin [17, 18].

The Thomson Reuters MarketScan^® research databases are comprised of only adjudicated claims; this minimizes, but not completely removes, the risk of incomplete, missing, or miscoded claims impacting the study findings. Errors present are likely random and independent of the study outcomes and cohorts, further minimizing their potential impact on the study. A related and significant limitation is the lack of records involving services that do not drive a service payment. Lab values (including hemoglobin A1C), patient biometric measures, and a record of free insulin samples are some of the key missing data fields. Further, the database contains very little information regarding physician behavior, training, or patient instructions, making it impossible to investigate or control for physician-level factors, including physician tendencies to prescribe more or less insulin per visit.

In a cohort of patients intensifying their basal insulin therapy with the addition of mealtime insulin, use was lower than expected in terms of quantity per day, number of claims, and persistence. In Addition, persistence to mealtime insulin decreases over time. Persistence to human insulin was considerably lower than the analog insulin. Elderly age, human insulin use, increased average insulin copayment, mental health comorbidity, and polypharmacy were all consistent predictors of poorer persistence with mealtime insulin.