Characteristics, Treatment Patterns, and Economic Outcomes of Patients Initiating Injectable Medications for Management of Type 2 Diabetes Mellitus in Japan: Results from a Retrospective Claims Database Analysis

Type 2 diabetes mellitus (T2DM), the most common form of diabetes, affected about 7.6% of adults aged 20–79 years in Japan in 2015 [1] and accounted for approximately 4% of the national healthcare expenditure in 2014 [2]. The healthcare costs are particularly high among patients who develop diabetes-related complications, as demonstrated by a Japanese claims data study in 2016 [3]. As such, it is important to effectively manage patients with T2DM in clinical practice. Japanese guidelines for the management of T2DM recommend beginning with lifestyle modifications such as diet and exercise therapy, followed by treatment with oral antidiabetic agents and/or injectable therapy if the glycemic control target is not achieved [4]. Injectable therapies may include the start of an insulin therapy (often basal insulin as the first step of insulin therapy) or glucagon-like peptide-1 (GLP-1) receptor agonists [4]. The Japanese treatment guidelines recommend a stepwise escalation of treatment (in terms of either dose or use of more than one therapeutic agent) along the course and progression of the disease. However, unlike other treatment guidelines such as from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), which recommend use of injectable medications among patients with a more advanced disease stage [5], the recommendations regarding the use of injectable medications and treatment pathway in Japan are not clear. With the increasing prevalence of T2DM [6], as well as the lack of specific recommendations regarding the use of injectable medications in Japan, there is a need for characterizing the treatment pathways followed in practice and subsequent outcomes in T2DM patients initiating injectable antidiabetic medications in Japan. In addition, a better understanding of the roles and relationships between the different types of Japanese health professionals treating T2DM patients is required to inform future policy decisions, particularly given the recent government initiatives to limit specialist care to supporting and advising of non-specialists when necessary [7].

To the best of our knowledge, however, no study to date has provided a comprehensive assessment of the treatment patterns and clinical as well as economic outcomes among T2DM patients initiating injectable antidiabetic medications—overall and by provider type—in Japan. For example, using a hospital-based database, Ikeda et al. [8] found varied treatment and healthcare service utilization patterns among Japanese patients with T2DM who initiated insulin therapy (long-acting, pre-mixed, rapid-acting, or a combination). However, only medium- and large-sized administrative hospitals were included, and outpatient clinics were not considered. In a different study, Hadjiyianni et al. [9] evaluated medication use and economic outcomes among patients initiating basal insulin in Japan and found that continuous use of basal insulin during the year after initiation was associated with lower medical resources and costs. However, the study was limited to basal insulin initiators and did not consider other injectable therapies. Additionally, neither study evaluated practice patterns and outcomes by type of provider prescribing insulin treatment. A few studies that did assess the variation between prescription patterns of general physicians (GPs) and specialists treating T2DM patients in Japan did not evaluate the treatment transitions leading up to and outcomes following insulin treatment. For example, in the insurance-based database, Hidaka et al. [10] found that more patients with T2DM were treated by GPs than by specialists, and prescription patterns between them were different. Specifically, the specialists were more likely to prescribe insulin (19% vs. 6%) and use intensified treatment approaches (e.g., triple combination therapy of biguanides + DPP-4 inhibitors + sulfonylureas) compared with GPs. Another study using administrative claims data from the Japan Medical Data Center also reported that patients treated in academic hospitals were more likely to receive aggressive treatment, including higher rates of insulin therapy, compared with those treated in clinics [11]. A different study surveyed more than 15,000 patients from clinics and hospitals in Japan and found that patients treated by diabetes specialists were more likely to initiate insulin than those treated by general practitioners [12].

To address this gap in the literature, using de-identified retrospective data for commercially insured patients in Japan, the objectives of this study were to: (1) understand the demographic and clinical characteristics of T2DM patients initiating injectable medications, (2) describe antidiabetic treatment patterns, clinical outcomes, and all-cause and T2DM-related medical resource use and costs during the 6 months before and 12 months after initiation of injectable medications, and (3) provide a better understanding of the types of providers prescribing the oral antidiabetic medications and medications for T2DM-related comorbidities prior to and following initiation of injectable antidiabetic medications. The outcomes were reported for the overall cohort as well as for cohorts stratified by type of medical provider, specialist, or GP, using as a proxy the setting in which the index medication was prescribed [hospital (including outpatient departments) for specialist or clinic for GP].

In this claims database study of T2DM patients initiating injectable antidiabetic medications in Japan, most (70%) of the patients initiating an injectable antidiabetic medication did so under specialist care as opposed to GP. Independent of the provider type, a large proportion of patients (almost 40%) did not use any antidiabetic medication in the 6-month period prior to initiating injectable medications, suggesting that in Japan, a substantial proportion of patients initiate injectable medications as the first-line treatment. These findings are similar to those reported by Kohro et al. [11] using the same database as the present study. Specifically, in their study of first-line antidiabetic medications, the authors found that nearly 20% of all T2DM patients initiated insulin as the first antidiabetic medication. The proportions were even higher among those treated in academic hospitals vs. clinics (~ 40% vs. ~ 10% in 2011) [11]. Despite the relatively young age (50 years on average), the population had high average HbA1c (8.9%) and fasting glucose levels as well as high rates of T2DM-related comorbidities and complications before initiating injectable medications; this suggests that the high disease burden prior to treatment initiation may have triggered a more intensified treatment approach, such as short-term intensive insulin therapy [18]. Indeed, in the DAWN Japan study, the physicians reported that they would consider initiating insulin at HbA1c levels ≥ 8.7%, and patients reported that insulin was recommended when average HbA1c levels were ≥ 9.6% [19].

In the current study, the average HbA1c levels at the last annual health check-up before the start of injectable antidiabetic medication were slightly higher for those treated by the GPs (9.1% GP vs. 8.8% specialist), suggesting that the GPs may use less intensive approaches to managing T2DM. In this study, patients treated by specialists were more likely to receive intensified treatment regimens involving rapid insulin only (37% vs. 10%) or basal-bolus treatment (26% vs. 8%) and less likely to receive basal insulin only (19% vs. 53%) compared with those treated by GPs. Additionally, over half of the patients used a combination of antidiabetic medications, including additional oral antidiabetic medications, during the follow-up period. These results are consistent with previous studies in Japan as well as other countries and highlight the considerable variation in physician practice patterns. For example, Ikeda et al. [8] studied Japanese patients with T2DM who initiated insulin therapy in a hospital setting and also concluded that only 11% of the patients were treated with long-acting insulin and that treatment with rapid insulin was the most common therapy (47% of initiators). Additionally, patients treated with more intensified treatments, including with rapid insulin, also tended to be older, have lower HbA1c, and experience more comorbid conditions. A survey of patients treated by general practitioners and diabetes specialists in Japan and a different study using the same database as the present study also found a similar pattern [11, 12]. Such findings could be attributed to the fact that GPs in Japan often have limited resources to facilitate initiation of injectable antidiabetic regimens. For example, in the aforementioned DAWN Japan study, nearly 55% of the non-specialist clinicians reported that “[they] do not have staff (nurse, pharmacists) who can assist with explanations” and that “[it] is difficult to provide guidance and education on insulin injection to patients” compared with 1% and 7% of the specialists reporting the same concerns [19]. With the limited number of diabetes specialists in Japan (4760 as of August 2013) [20], providing adequate education and support systems to the GPs may help improve the management of T2DM patients.

Regarding the outcomes after injectable initiation, we find that patients continued treatment with the index medication for approximately 7 months, independent of the setting in which the treatment was initiated. These findings are consistent with previous research that demonstrated that the probability of discontinuing basal insulin treatment within the first year after initiation in Japan was low (22%) [9]. Despite this, the patients in our sample had considerable resource use and costs in the year after treatment initiation, a finding also consistent with the previously mentioned study by Hadjiyianni et al. [9]. In particular, 55% of all patients had at least one hospitalization in the year after injectable initiation; the average all-cause costs during the 12-month follow-up period were ¥1856,727, approximately 90% of which were attributable to T2DM and related complications and comorbidities. The economic burden was even higher among those initiating the injectable medication with a specialist. Specifically, nearly three-quarters (73%) of the patients in the specialist cohort had an inpatient visit during the 12-month follow-up period compared with 12% in the GP cohort, and among those with an inpatient visit, the average number of inpatient days was significantly higher for patients in the specialist cohort. Consequently, patients in the specialist cohort had higher medical costs relative to those in the GP cohort. However, differences in pharmacy costs across the two cohorts were small. Taken together, our findings suggest that the considerable increase in the proportion of patients with an inpatient visit during the follow-up period was the major driver of the cost increase for patients in the specialist cohort. It is possible that the higher rates of hospital visits are related to continued care management in a hospital setting because of the complexity of the treatment and higher comorbidity burden in the specialist cohort. However, our findings indicate that independent of the index medication setting, after initiating the injectable medication, routine follow-up care may transition to a clinic setting. Specifically, 64% of patients who initiated injectable medications in a hospital setting received their most recent injectable medication during the follow-up period in a clinic setting. Most patients also received their oral medications as well as medications for T2DM-related complications and comorbidities from the same providers, suggesting that use of hospitals and both specialist and GPs for maintenance treatment of T2DM and related conditions is limited. Given this observation, an alternative explanation for the higher observed costs could be related to differences in practice patterns by provider specialty and/or other, unobserved patient characteristics. While this was not studied directly in the present study, Chin et al. [21] studied the differences in resource utilization among older patients with diabetes in the US who were cared for by endocrinologists, internists, family practitioners, and general practitioners and concluded that patients treated by specialists (endocrinologists and internists) had higher utilization of diabetes-specific process-of-care measures and received a more costly style of care than patients treated by family practitioners and general practitioners. Additional research is warranted to understand how hospital- and clinic-based physicians communicate treatment strategies for T2DM and T2DM-related complications/comorbidities, including who makes the decisions to augment or switch treatments as patients’ conditions progress over time and whether patients are referred to specialists in a timely fashion for initiating more complicated treatment regimens.

To the best of our knowledge, this is the first study to provide a comprehensive assessment of the characteristics and outcomes among patients with T2DM initiating their first injectable medication with or without prior oral antidiabetic treatment in Japan, both before and after treatment initiation, using real-world health insurance data. Additionally, the study provides important insight into the characteristics and outcomes of patients treated by specialists (i.e., in a hospital inpatient or outpatient setting) compared with those treated by general practitioners in Japan, which could help inform future policy decisions regarding the coordination of care between different types of providers. This study particularly benefits from the large sample size of the JMDC claims database as well as from the availability of laboratory measures from annual health check-ups. Another advantage of the JMDC database is that it contains a classification of the medical facilities associated with each claim, which aided in the construction of the two study cohorts to approximate provider specialty. However, this analysis was subject to limitations associated with any inaccuracies or incompleteness of the ICD-10 codes and ATC codes used to identify diagnoses and medication use as well as lack of clinical information (e.g., to assess blood glucose control). Relatedly, while the methods used to identify patients with T2DM are consistent with prior studies using the same database, the effect of alternative criteria for identifying T2DM patients on the study findings is not known [3]. In addition, HIV/AIDS information was not available in JMDC, so the CCI may not be precise. Similarly, the specialty of the treating physician was not directly observed in the data, and the proxy used to approximate this attribute may not accurately represent care provided by specialists in hospitals with < 20 beds or by GPs in large hospitals. The JMDC data on laboratory test results were limited to tests performed as a part of the regular annual check-ups for beneficiaries aged at least 40 years and did not include information from tests performed for other reasons (e.g., while in the hospital). Further, the results were limited to tests performed at special facilities performing health check-ups or hospital/clinics recommended by the beneficiaries’ insurance provider for their routine annual check-up. Furthermore, findings are limited to people aged under 75 years who have employer-sponsored insurance in Japan and may not generalize to other populations (e.g., may not be representative of patients covered by other insurance programs) as the JMDC database is not representative of the national population in Japan.

The study findings indicate that in Japan patients with T2DM are more likely to initiate medications with specialists as opposed to GPs. Patients initiating injectable medications with specialists are older and have greater disease severity prior to treatment initiation, but are less likely to be using oral antidiabetic medications in the 6 months prior to initiating injectable medications than patients initiating injectable medications with GPs. Additionally, patients initiating injectable medications with specialists are more likely to receive intensive treatment with rapid insulin or basal-bolus therapy on their index date than those initiating treatment in a clinic setting and are more likely to have inpatient visits and higher healthcare costs both before and after treatment initiation. However, the majority of patients initiating injectable antidiabetic medications with specialists receive subsequent injectable medication during the follow-up period from the GPs, suggesting that GPs are responsible for maintenance care as opposed to the prescribing specialists. Further research is needed to understand the reasons behind the prescribing patterns and subsequent outcomes among T2DM patients in Japan, as well as to better understand the communication channels between GPs and specialists regarding patients’ treatments over time.