The INITIATOR Study: Pilot Data on Real-World Clinical and Economic Outcomes in US Patients with Type 2 Diabetes Initiating Injectable Therapy

This retrospective analysis used medical and pharmacy claims, enrollment information, and linked electronic laboratory results from two independent administrative claims databases associated with OptumInsight™ (OI; Eden Prairie, MN, USA) and HealthCore^® (HC; Wilmington, DE, USA) in the United States (US). Commercially insured adults (and Medicare Advantage adults in the HC database) were eligible for the study if they were aged 18 years or older and had T2DM, defined as having one or more inpatient visits or two or more outpatient visits (≥30 days apart) with a primary or secondary diagnosis of T2DM [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes: 250.x0 or 250.x2], as used in previously published claims-database studies [11‐13]. To be included, patients were required to have initiated either insulin glargine by prefilled pen device or liraglutide (with index date as the earliest fill) between January 1, 2010 and June 30, 2010 (HC) or July 31, 2010 (OI) and have received one or more OAD in the 6 months before the index date (baseline). Patients were required to have continuous medical and pharmacy benefits for the baseline period and 9 (OI) or 12 (HC) months after index date (follow-up). In the OI database only, one or more glycated hemoglobin A_1c (A1C) values in the baseline period through 15 days following the index date was also an inclusion criterion. In the A1C analyses, for consistency, a sub-sample of patients with available baseline A1C values was used in the HC database as well.

Patients were excluded from the study if they met any of the following criteria: one or more pharmacy claims for insulin, exenatide, liraglutide, or pramlintide during the baseline period; pharmacy claims for both insulin glargine (in either pen or vial form) and liraglutide on the index date; pharmacy claims for insulin glargine in prefilled pen format and insulin glargine in other forms (vial-and-syringe, reusable pen) on the index date. Patients with Medicare Supplemental or Part D were excluded, as not all claims are available for these patients; the HC database retained patients with Medicare Advantage enrollment, as they have full claims representation.

This retrospective analysis is based on previously collected data and does not involve any new studies of human subjects performed by any of the authors.

Baseline factors were recorded, including demographics, comorbidities [including modified Quan–Charlson comorbidity index (QCI) [14] and obesity as identified with ICD-9-CM codes], hypoglycemic events, prescription drug usage, and, where available, A1C. Health care resource utilization included emergency department (ED) visits, inpatient hospitalizations, ambulatory visits, and endocrinologist visits, as well as any hospitalization in the 30 days before the index date. Diabetes-related health care resource utilization was also analyzed and included claims with a primary or secondary diagnosis of diabetes (ICD-9-CM: 250.xx). Health care costs were computed as the combined patient- and plan-paid amounts of adjudicated claims. Costs were adjusted to 2011 US dollars using the medical care component of the US consumer price index [15]. Diabetes-related health care costs included costs from medical claims with a primary or secondary diagnosis of diabetes (ICD-9-CM: 250.xx), anti-diabetic medications, glucose meters, and test strips.

Clinical outcomes analyzed at follow-up (9 months for OI and 12 months for HC) were A1C change from baseline, treatment persistence, daily average consumption (DACON), and hypoglycemia. Treatment persistence was defined as remaining on the study drug during the follow-up period without discontinuation or switching after study drug initiation [16‐19] and medication was considered discontinued if the prescription was not refilled within the expected time of medication coverage (the 90th percentile of the time, stratified by the metric quantity supplied, between first and second fills among patients with at least one refill in the specific cohort, irrespective of post index eligibility). Patients who restarted their initial medication after having met the criteria for discontinuing their index medication were considered to be non-persistent. For patients using the insulin glargine pen, persistence rates were based on all insulin glargine fills because patients on insulin glargine pen could switch to vial-and-syringe as their insulin delivery device but would still be on insulin glargine treatment. DACON was calculated as the total amount of medication (units or mg) dispensed before the last refill of the study drug divided by the total number of days between initiation and last refill during follow-up. While DACON is not comparable between insulin glargine and liraglutide medications, it was reported as part of the respective cohort profiles. Hypoglycemia was defined as a health care encounter (outpatient, inpatient, or ED visit) with a primary or secondary ICD-9-CM diagnosis code for hypoglycemia (ICD-9 code 250.8x–diabetes with other specified manifestations; 251.0–hypoglycemic coma; 251.1–other specified hypoglycemia; or 251.2–hypoglycemia, unspecified) [20].

Due to the differences in the baseline demographics and clinical characteristics of these treatment groups, clinical outcomes were described, and health care resource utilization and costs were compared between baseline and follow-up within each treatment group, rather than comparing outcomes between treatment groups. Follow-up health care costs (adjusted to 2011 US dollars) and resource utilization were also computed, using definitions consistent with those created in the baseline period.

This study used an intent-to-treat approach, in which patients who augmented or switched from their initial treatment regimen were retained in their assigned cohort. This approach best captures what the prescribing physician intended for the patient to take. Furthermore, any deviations from the initial treatment are reflective of how the medication is being used in the real-world setting. Baseline characteristics, treatment patterns, and outcomes among the insulin glargine pen and liraglutide groups were assessed descriptively. Baseline characteristics and study outcomes were compared using unadjusted statistical comparisons for both study cohorts. Continuous variables were compared using Student t tests (for the OI cohort) or Student t tests and Wilcoxon rank-sum tests (for the HC cohort), while categorical variables were compared using Fisher exact tests (for the OI cohort) and χ ² tests (for the HC cohort), depending on the distribution of the measure. Due to demographic and clinical differences observed in the insulin glargine pen and liraglutide cohorts during the baseline period, follow-up outcomes were assessed descriptively. Within each treatment group, annualized diabetes-related health care costs were compared between the baseline and follow-up periods using paired t tests. The statistical analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, NC, USA; 2008).

Data from a total of 2,570 patients were included: 861 OI (insulin glargine pen n = 498, liraglutide n = 363) and 1,709 HC (insulin glargine pen n = 1,188, liraglutide n = 521). There were substantial differences in the demographics and baseline clinical characteristics between patients initiating insulin glargine pen and those initiating liraglutide (Table 1). In both databases, patients initiating insulin glargine pen were more likely to be male, have poorer baseline health (as measured by the modified QCI), and be treated with sulfonylureas at baseline. Patients initiating treatment with liraglutide were more likely to be obese or have hyperlipidemia.

Baseline A1C measures were available for all patients included from the OI database, and in this database the insulin glargine pen cohort had a higher mean A1C than the liraglutide group (insulin glargine: 9.8% and 9.1% versus liraglutide: 7.9% and 7.7%, OI and HC, respectively, both P < 0.001; Table 1). Prior to injectable therapy initiation, A1C was already within the American Diabetes Association target range of <7.0% [1] for more of the liraglutide-using patients than the insulin glargine pen initiators (29.5% versus 9.2%, P < 0.001), while baseline A1C was ≥9.0% for fewer of the liraglutide initiators compared to insulin glargine pen initiators (21.8% versus 60.0%, P < 0.001; Fig. 1). Among patients in the HC database with baseline A1C data available [insulin glargine pen n = 283 (24%), liraglutide n = 113 (22%)], baseline mean A1C levels were also higher among those using the insulin glargine pen compared to liraglutide. In this subset, baseline A1C was also <7.0% for more patients using liraglutide than insulin glargine pen (33.6% versus 11.3%, P < 0.001) and ≥9.0% for more patients with insulin glargine pen than liraglutide (47.7% versus 16.8%, P < 0.001). Hypoglycemia during the baseline period was infrequent in both groups (Table 1).

Baseline health care utilization and costs were significantly different between cohorts, with a higher percentage of insulin glargine patients experiencing diabetes-related ED visits and hospitalizations in the 30 days prior to injectable therapy initiation (Table 1). Annualized all-cause total health care costs at baseline were either similar or higher for the insulin glargine pen cohort versus the liraglutide cohort, depending on the database [OI $15,050 (median $5,708) versus $10,812 ($6,541), P = 0.020; HC $15,899 ($6,637) versus $11,912 ($7,608), P = 0.137]. The annualized diabetes-related costs for insulin glargine pen initiators compared to liraglutide initiators followed a similar pattern [OI $8,344 ($2,269) versus $4,510 ($2,503), P = 0.006; HC $7,094 ($2,478) versus $4,136 ($2,164), P = 0.126; Fig. 2].

For those patients with A1C values available at both baseline and follow-up, mean A1C reduction with insulin glargine pen was 1.11% over 9 months (OI; n = 253 with mean baseline A1C = 9.65%) and 0.75% over 12 months (HC; n = 86 with mean baseline A1C = 8.97%). Mean A1C reduction with liraglutide was 0.58% over 9 months (OI; n = 174 with mean baseline A1C = 8.00%) and 0.38% over 12 months (HC; n = 40 with mean baseline A1C = 7.61%). In patients with A1C ≥7.0% at baseline (OI: insulin glargine n = 229 with mean baseline A1C = 9.98%, liraglutide n = 125 with mean baseline A1C = 8.66%; HC: insulin glargine n = 79 with mean baseline A1C = 9.20%, liraglutide n = 26 with mean baseline A1C = 8.31%), A1C <7.0% was reached during follow-up in 21% and 15% with insulin glargine and 34% (OI) and 38% (HC) with liraglutide.

Treatment persistence among patients using insulin glargine was 61% in the OI database and 60% in the HC database. For patients using liraglutide, treatment persistence was 52% in the OI database and 51% in the HC database. Mean persistence duration was 233 days and 305 days for insulin glargine and 207 days and 264 days for liraglutide in the OI (follow-up 270 days) and HC databases (follow-up 365 days), respectively (Fig. 3). The DACON of insulin glargine was 29.9 and 28.0 IU, and the DACON for liraglutide was 1.14 and 1.44 mg, for the OI and HC databases, respectively.

The hypoglycemia event rate for insulin glargine pen users was 0.11 (OI database) and 0.25 (HC database) events per patient year; for liraglutide users, it was 0.06 events per patient year in both databases. The percentage of patients experiencing a hypoglycemic event in the 9-month follow-up of the OI database was 4.4% and 3.0% for the insulin glargine pen and liraglutide cohorts, respectively. For the HC database the percentage experiencing at least one hypoglycemic event in the 12-month follow-up was 6.2% with insulin glargine pen and 2.3% with liraglutide.

During 9-month (OI database) and 12-month (HC database) follow-up, respectively, a diabetes-related ED visit occurred in 5% and 12% of patients with insulin glargine and 2% and 7% of patients with liraglutide. Furthermore, a diabetes-related ambulatory visit occurred in 97% and 98% of patients with insulin glargine and 94% and 98% of patients with liraglutide. Finally, an endocrinologist visit occurred for 33% and 30% of patients with insulin glargine and 31% and 34% of patients with liraglutide. Total annualized all-cause health care costs in the follow-up period for the insulin glargine pen cohort were $16,078 (median $7,449) and $16,466 ($9,183) for the OI and HC databases, respectively. Annualized diabetes-related costs among insulin glargine pen-using patients remained similar from baseline to follow-up in both the OI and HC databases ($8,344 versus $7,749 OI, and $7,094 versus $7,731 HC; Fig. 2). There was a significant increase in pharmacy costs in the follow-up period in both databases, but this was offset by non-significant decreases in diabetes-related medical costs (Fig. 2). For the liraglutide initiators, total annualized health care costs in the follow-up period were $15,410 ($9,919) and $14,579 ($10,244) in the OI and HC databases, respectively. Annualized diabetes-related costs among patients initiating liraglutide increased from baseline to follow-up in both the OI and HC databases ($4,510 versus $7,731 OI, and $4,136 versus $7,111 HC; both P < 0.001; Fig. 2). There was a significant increase in pharmacy costs for both databases, with smaller increases for medical costs (which did not meet statistical significance), contributing to the higher diabetes-related costs.