Immune Checkpoint Inhibitor Is Associated with Improved Survival in Advanced Non-small Cell Lung Cancer Occurring in Patients with Autoimmune Disease

Abstract

The use of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, clinical trials often exclude those with a history of autoimmune diseases (ADs) because of concerns regarding immune-related adverse events. Therefore, the efficacy of ICIs in advanced NSCLC patients with ADs should be evaluated. This study used administrative claims data from advanced treatment centers in Japan and identified patients with advanced NSCLC who began chemotherapy between December 2016 and January 2023. The patients were divided into four groups based on the presence of ADs and types of chemotherapy received. The association between ICI therapy and overall survival in the subgroups with or without ADs, and the association between the presence of AD and overall survival in patients who received ICI therapy and conventional chemotherapy, were analyzed using Cox proportional hazard regression, including therapy and presence of ADs and their interaction as covariates. These results were obtained using the inverse probability of treatment weighting. ICI therapy had a hazard ratio (95% confidence interval) for death in the subgroup of AD and non-AD patients of 0.88 (0.84–0.92) and 0.83 (0.71–0.97), respectively (p = 0.459 for interaction). For some specific ADs, including type 1 diabetes mellitus, the association between ICI therapy and decreased mortality was not observed. In conclusion, our study showed comparable associations between ICI therapy and reduced mortality in AD and non-AD subgroups of patients with advanced NSCLC. However, therapy strategies tailored to each AD type and thorough discussions regarding the risk-benefit profile are crucial.

INTRODUCTION

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC). They improve survival of patients with advanced NSCLC compared to chemotherapy alone and are now approved as frontline therapy, either as single agents^1–3) or in combination with cytotoxic chemotherapy.^4–8) ICIs exert their therapeutic effects by targeting receptors that are vital for maintaining immunologic homeostasis. However, immunotherapy may trigger serious and potentially fatal immune-related adverse events (irAEs). Consequently, clinical trials of ICIs for patients with advanced NSCLC have generally excluded patients with a history of autoimmune diseases (ADs) over concerns of increased risk of developing severe irAEs. On the other hand, patients with ADs face an increased risk of developing cancer due to abnormalities in immune function and immune modulatory therapy. Notably, an estimated 13.5–24.6% of lung cancer patients have been diagnosed with ADs.⁹⁾

Several studies have evaluated the safety and efficacy of ICIs in NSCLC patients with ADs.^10–15) A meta-analysis study reported that, in advanced cancer patients, overall survival (OS) for patients receiving ICI therapy was similar regardless of the presence of ADs.¹⁶⁾ However, this meta-analysis study also reported that the estimated associations of ADs with OS in patients with ICIs were highly heterogeneous among studies, possibly due to a variety of reasons, including diverse AD types of each study. These facts suggested the importance of careful evaluation of ICIs efficacy focusing on each type of ADs. Furthermore, most earlier studies compared the survival of ICI-treated patients with and without ADs, based on the assumption that the presence of ADs does not affect mortality. However, the presence of ADs may be associated with increased mortality in patients with advanced NSCLC,¹⁷⁾ and the efficacy of ICIs for advanced NSCLC patients with ADs should be evaluated considering this point.

Our study aimed to comprehensively address a diverse range of ADs using administrative claims data for the examination of the association between ICI therapy and OS in advanced NSCLC patients with ADs. Patients receiving ICI therapy as well as those receiving conventional chemotherapy were included for comparison. Additionally, analyses focusing on each type of ADs were also explored.

MATERIALS AND METHODS

Data Source

This study used administrative claims data obtained from advanced treatment centers in Japan. The Medical Data Vision (MDV), Tokyo, Japan, provided data on patients diagnosed with lung cancer (C34, as per the International Classification of Diseases, 10th Revision [ICD-10]) between April 1, 2008, and January 31, 2023. MDV’s database includes more than 38 million patients and comprises 23% of all Diagnostic Procedure Combination/Per Diem Payment System (DPC/PDPS) hospitals in Japan.¹⁸⁾ The DPC/PDPS system represents a diagnosis procedure combination per-diem payment system, which ensures fixed daily compensation based on diagnosis grouping.¹⁹⁾ This system, adopted by most designated acute care hospitals, categorizes patients as DPC based on the combination of diagnoses and procedures performed during hospitalization.²⁰⁾ The dataset included routinely collected patient information encompassing both outpatient and inpatient medical care, such as ’basic patient characteristics (age, sex, weight, and height), hospitalization dates, diagnoses based on ICD-10 codes, survival status, and individual medical practice details. MDV’s database has been used in multiple clinical studies on lung cancer.^21–23)

Study Population

The study included patients aged ≥18 years who received chemotherapy for new advanced NSCLC between December 2016 and January 2023, during which time pembrolizumab had been covered by insurance for first-line chemotherapy in patients with NSCLC since December 2016. To identify patients who received first-line chemotherapy after lung cancer diagnosis, we included those with a minimum 3-month interval from database entry to the date of first lung cancer diagnosis. The index date was defined as the first date of chemotherapy. To identify patients with advanced NSCLC, patients who received chemoradiotherapy or adjuvant chemotherapy were excluded from this study, following methods similar to a previous study by Jacob et al.¹⁷⁾ We also excluded patients receiving therapy drugs targeting driver mutations. Exclusion criteria are shown in Supplementary eMethod 1. Practice codes used to identify patients with driver mutations are shown in Supplementary eTable 1-1. Patients were classified into four groups: ADs + ICIs, Non-ADs + ICIs, ADs + Non-ICIs, Non-ADs + Non-ICIs), representing patients with or without ADs who received ICI or conventional chemotherapy as first-line chemotherapy.

Identification of Autoimmune Diseases

The study included specific qualifying ADs: systemic sclerosis (SSc), myositis, rheumatoid arthritis (RA), Sjögren’s syndrome, systemic lupus erythematosus (SLE), mixed connective tissue disease/overlap syndromes, autoimmune disease-associated interstitial lung disease, Hashimoto’s thyroiditis, celiac disease, graves’ disease, type 1 diabetes mellitus (DM), vitiligo, rheumatic fever, pernicious anemia/atrophic gastritis, alopecia areata, immune thrombocytopenic purpura, multiple sclerosis, temporal arteritis, Crohn’s disease/ulcerative colitis, antiphospholipid syndrome, autoimmune hepatitis type 1, primary biliary cirrhosis, Addison’s disease, dermatitis herpetiformis, Kawasaki disease, sympathetic ophthalmia, HLA-B27-associated acute anterior uveitis, and myasthenia gravis. ADs were identified using ICD-10 codes described in Supplementary eTable 1-2. Identification of patients with ADs required at least one ICD-10 code for ADs entered prior to the month before the index date and a confirmed AD diagnosis. The presence of autoimmune disease-associated interstitial lung disease was determined based on the registration of other ADs and the definitive diagnostic registration of Interstitial lung disease/Idiopathic pulmonary fibrosis/Pulmonary fibrosis after computed tomography evaluation. The medical procedures for computed tomography are detailed in Supplementary eTable 1-3.

Identification of Death

Survival status and date of death were derived from discharge summaries. Survival analyses were performed for survival data within a 3-year follow-up period after the initiation of first-line therapy (index date).

Demographic and Clinical Information

The following demographic and clinical characteristics were identified: age, sex, body mass index (BMI), smoking status, histology of NSCLC, Charlson comorbidity index (CCI),²⁴⁾ Barthel index,²⁵⁾ treatment dates, and medication (immunosuppressant). The identification process of demographic and clinical characteristics is summarized in Supplementary eMethod 2.

Statistical Analysis

Demographic and clinical characteristics of patients were summarized using median and interquartile range (IQR) for continuous variables and numbers (percentage) for categorical variables.

A propensity score approach with inverse probability of treatment weighting (IPTW) was applied to address confounding among the four groups based on therapy and the presence of ADs. Probabilities for group allocation were estimated using multinomial logistic regression, including the following observed potential confounders: age, sex, BMI, smoking status, histology of NSCLC, CCI, Barthel index, and treatment dates.

OS probabilities were estimated using the Kaplan–Meier method. Associations of the presence of ADs and ICI therapy with OS were evaluated using Cox proportional hazard regression. Covariates included the presence of any AD, types of chemotherapy, and their interactions. Hazard ratios (HRs) for ICI therapy among groups with or without ADs (comparison 1) and HRs for AD presence among groups who received ICI or conventional chemotherapy (comparison 2) were estimated. IPTW adjustment was applied to all analyses. The main target of the assessment was the presence or absence of interaction effect between the presence of any ADs and chemotherapy types on OS. ICI therapy was also analyzed separately by treatment effect type: programmed cell death-1 (PD-1) (atezolizumab) or programmed death-ligand 1 (PD-L1) (pembrolizumab, nivolumab) (including in combination with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) (ipilimumab)). Additionally, a sensitivity analysis was conducted, excluding them as outliers from the standpoint of etiology, due to the rarity of NSCLC cases in individuals in their <40 years.

For subgroup analyses, Cox proportional hazard regressions that narrowed analysis targets to the presence of each specific AD were performed, and HRs for ICI therapy among subgroups with each specific ADs were evaluated.

Missing covariate data were managed through multiple imputation methods using predictive mean matching. Statistical analyses were conducted using R version 4.2.2 (R Core Team²⁶⁾) software.

Ethics Statement

The utilization of anonymized data exempts clinical studies from the application of the Japanese Ethical Guidelines for Medical and Biological Research Involving Human Subjects.²⁷⁾ In our study, MDV anonymized the provided data; therefore, obtaining informed consent was deemed unnecessary.

RESULTS

Study Populations and Their Characteristics

The study included data from 55165 patients (aged ≥18 years) newly diagnosed with NSCLC who started chemotherapy (ICI or conventional chemotherapy) from December 2016 to January 2023. Among these, 31053 met the study eligibility criteria for patients with advanced NSCLC (Fig. 1). Of these, 2683 (8.6%) patients had ADs and underwent therapy as follows: 47.6% (1277/2683) received ICI as first-line therapy, and the remaining 52.4% (1406/2683) received conventional chemotherapy. Additionally, 28370 (91.4%) patients without ADs underwent therapy as follows: 45.1% (12785/28370) received ICI as first-line therapy, and the remaining 54.9% (15585/28370) received conventional chemotherapy.

Fig. 1. Flow Chart of Patient Inclusion and Categorization Based on the First-Line Chemotherapy Received (ICI or Conventional Chemotherapy) and Presence of Autoimmune Diseases

NSCLC, non-small cell lung cancer; NSCLC, non-small cell lung cancer; ADs, autoimmune diseases; ICI, immune checkpoint inhibitor.

Table 1 summarizes the demographic and clinical characteristics of the study population. No clear differences in sex, age, BMI, and smoking status were observed among the four groups. In both therapy subgroups, CCI value was higher in the AD subgroups. In the ADs + ICIs and ADs + Non-ICIs subgroups, 96 (7.5%) and 374 (26.6%) patients, respectively, received immunosuppressive drugs. Details of immunosuppressive drugs in patients with ADs are presented in Supplementary eTable 2.

Table 1. Characteristics of Patients with Advanced NSCLC

	With ADs (n = 2683)		Without ADs (n = 28370)
	ICI therapy (n = 1277)	Conventional chemotherapy (n = 1406)	ICI therapy (n = 12785)	Conventional chemotherapy (n = 15585)
Patient characteristics	Median (IQR) or n (%)	Median (IQR) or n (%)	Median (IQR) or n (%)	Median (IQR) or n (%)
Age (years)	72.0 (66.0, 77.0)	71.0 (66.0, 76.0)	72.0 (65.0, 77.0)	72.0 (66.0, 77.0)
BMI (kg/m2)a)	21.7 (19.4, 24.3)	21.9 (19.8, 24.2)	21.7 (19.5, 24.0)	22.0 (19.7, 24.3)
Sex
Male	942 (73.8%)	923 (65.6%)	10331 (80.8%)	11813 (75.8%)
Female	335 (26.2%)	483 (34.4%)	2454 (19.2%)	3772 (24.2%)
Smoking status (current/past)a)	972 (79.7%)	1024 (75.6%)	9905 (81.6%)	11283 (76.1%)
Histology of NSCLCa)
Adenocarcinoma	668 (73.7%)	706 (73.0%)	6716 (74.3%)	7780 (76.0%)
Squamous cell carcinoma	238 (26.3%)	261 (27.0%)	2320 (25.7%)	2461 (24.0%)
CCI
0–2	772 (60.5%)	864 (61.5%)	10522 (82.3%)	13394 (85.9%)
≥3	505 (39.5%)	542 (38.5%)	2263 (17.7%)	2191 (14.1%)
Barthel indexa)
=100	1013 (88.0%)	1145 (90.6%)	10010 (88.3%)	12320 (89.7%)
<100	138 (12.0%)	119 (9.4%)	1326 (11.7%)	1410 (10.3%)
Treatment dates
2016/01/01–2019/12/31	388 (30.4%)	643 (45.7%)	4157 (32.5%)	8740 (56.1%)
2020/01/01–2023/01/31	889 (69.6%)	763 (54.3%)	8628 (67.5%)	6845 (43.9%)
Medication
Immunosuppressant	96 (7.5%)	374 (26.6%)	26 (0.2%)	163 (1.0%)

a) For BMI, smoking status, histology of NSCLC, and Barthel index, there were missing data for 7.9, 4.9, 31.9, and 11.5% of the total patients, respectively. NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor; ADs, autoimmune diseases; IQR, interquartile range; BMI, body mass index; CCI, Charlson comorbidity index.

Supplementary eTable 3 outlines the types of ADs in this study. RA accounted for most ADs. There was a tendency toward selecting ICIs as first-line therapy for autoimmune endocrine disorders such as type 1 DM and Hashimoto’s thyroiditis.

ICI Therapy

Supplementary eFig. 1 shows the changes in the use of ICIs over time. Pembrolizumab accounted for a large proportion of prescriptions after insurance coverage of pembrolizumab in first-line chemotherapy for patients with NSCLC, but nivolumab (including in combination with ipilimumab) and atezolizumab are increasingly prescribed at present. Additional details of ICI treatment in the ADs + ICIs and Non-ADs + ICIs groups are presented in Supplementary eFig. 2 and Supplementary eTable 4. The types of ADs in more than 50 patients who received ICI therapy are shown in Fig. 2. In the ADs + ICIs group, 961 (75.3%) patients received a pembrolizumab regimen, 198 (15.5%) patients received a nivolumab (including in combination with ipilimumab) regimen, and the remaining 118 (9.2%) patients received atezolizumab regimen. The median number of treatment cycles for pembrolizumab, nivolumab (including in combination with ipilimumab), and atezolizumab in the ADs + ICIs group were 5, 4, and 3, respectively. In more than 50 patients with ADs who received ICI therapy, patients with type 1 DM had the lowest median number of treatment cycles.

Fig. 2. Details of ICI Treatment (Patients without and with ADs)

^aIncluding in combination with ipilimumab. ^bTypes of ADs in more than 50 patients who received ICI therapy are shown. ICI, immune checkpoint inhibitor; ADs, autoimmune diseases.

Survival Outcomes

Using the IPTW method, analyses were conducted to control for the effects of observed potential confounders. The IPTW-balanced characteristics of the four patient populations are outlined in Supplementary eTable 5. Survival curves for the four groups estimated using the Kaplan–Meier method with IPTW adjustment are shown in Fig. 3A. Survival curves of those comparing patients treated with ICI and conventional chemotherapy among patients with or without ADs are shown in Figs. 3B and C, respectively. Similarly, survival curves of those comparing patients with and without ADs among patients treated with ICI or conventional chemotherapy are shown in Figs. 3D and E, respectively. Results from Cox proportional hazard analyses with IPTW adjustment are summarized in Table 2. Both AD and non-AD patient groups showed similar associations with ICI therapy, each with reduced mortality (HRs for death of 0.88 (95% confidence interval (CI): 0.84–0.92) and 0.83 (95% CI: 0.71–0.97), respectively (comparison 1). When the use of ICI therapy status was further classified by therapeutic effect types, the hazard ratios exhibited similar patterns as the main results (Supplementary eFig. 3). In both conventional and ICI therapy patient groups, the presence of ADs was similarly associated with increased mortality, with HRs for death of 1.16 (95% CI: 1.04–1.28) and 1.09 (95% CI: 0.96–1.24), respectively (comparison 2). There was no significant interaction effect on OS between the presence of ADs and ICI therapy (p = 0.459 for interaction). The results of the sensitivity analysis for patients ≥40 years were also consistent with the main analysis (Supplementary eFig. 4).

Fig. 3. The Estimated Kaplan–Meier Curves Adjusted with the IPTW Method

ADs, autoimmune diseases; ICI, immune checkpoint inhibitor; IPTW, inverse probability of treatment weighting; HR, hazard ratio; CI, confidence interval.

Table 2. Assessment for Interaction Effect of ADs and ICI Therapy on Overall Survival

Population	Outcome	Comparison	HRa) for death (95% CI)	p-Value
Patients without ADs	Deathb)	ICIs (ref. Non-ICIs)	0.88 (0.84–0.92)	<0.001
Patients with ADs	Deathb)	ICIs (ref. Non-ICIs)	0.83 (0.71–0.97)	0.020
Patients who received conventional chemotherapy	Deathb)	With ADs (ref. Without ADs)	1.16 (1.04–1.28)	0.006
Patients who received ICI therapy	Deathb)	With ADs (ref. Without ADs)	1.09 (0.96–1.24)	0.201

a) HRs were estimated after balancing the following variables by the inverse probability of treatment weighting method: age, sex, BMI, smoking status, histology of NSCLC, CCI, and treatment dates. b) Survival after 3 years from the index date was censored. There was no significant interaction effect of ADs and ICI therapy on overall survival (p = 0.459 for interaction). ADs, autoimmune diseases; ICI, immune checkpoint inhibitor; HR, hazard ratio; CI, confidence interval; BMI, body mass index; CCI, Charlson comorbidity index; NSCLC, non-small cell lung cancer.

The associations between ICI therapy and OS in patients without ADs and patients with each type of ADs are shown in Supplementary eFig. 5. The types of ADs in more than 50 patients who received ICI therapy are shown in Fig. 4. For patient subgroups with SSc, myositis, RA, SLE, pernicious anemia/atrophic gastritis, and myasthenia gravis, the point estimates were roughly consistent with that of patients without ADs. The results were inconclusive for other types of ADs. For type 1 DM, the point estimate indicated the associations between ICI therapy and increased mortality.

Fig. 4. Forest Plot of Hazard Ratios for ICI Therapy from the Subgroup Analysis

^aThere was no significant interaction effect of ADs and ICI therapy on overall survival (p = 0.459 for interaction). ^bTypes of ADs in more than 50 patients who received ICI therapy are shown. AD, autoimmune disease; ICI, immune checkpoint inhibitor; HR, hazard ratio; CI, confidence interval.

DISCUSSION

For both populations of advanced NSCLC patients, with or without ADs, ICI therapy was similarly associated with lower mortality. Roughly similar relationships of ICI therapy with decreased mortality to that of patients without ADs were observed for patients with SSc, myositis, RA, SLE, pernicious anemia/atrophic gastritis, and myasthenia gravis. The presence of ADs was similarly associated with increased mortality in both populations of advanced NSCLC patients, those who received ICI or conventional chemotherapy.

In the advanced NSCLC patient population, ICI therapy was associated with a similar reduction in mortality, irrespective of the presence of ADs. This trend can be attributed to certain factors. The emergence of irAEs has been associated with prolonged survival in NSCLC patients treated with ICI.²⁸⁾ A recent study has highlighted the potential of mild irAEs to improve prognosis in NSCLC patients.²⁹⁾ These studies suggest that an appropriate autoimmune response may contribute to improved prognosis in lung cancer patients treated with ICI. The same mechanism may have been responsible for the improved prognosis in advanced NSCLC patients with ADs receiving ICI therapy.

In the subgroup of patients with type 1 DM, the point estimate indicated the associations between ICI therapy and increased mortality, which may be attributed to inadequate ICI therapy. Indeed, our study revealed that patients with type 1 DM underwent the lowest number of ICI treatment cycles compared to those in other ADs in Fig. 2. This may be linked to the complex management requirements of type 1 DM exacerbated by ICI therapy. The treatment regimen necessitates discontinuing ICI therapy, coupled with electrolyte replacement and insulin therapy until clinically stable glycemic control is attained.^30–32) In addition, type 1 DM triggered by ICI can develop as a fulminant form. As a result, controlling blood glucose levels due to exacerbation of type 1 DM is difficult and may increase the risk of death due to diabetic ketoacidosis.³³⁾ Considering these safety concerns, ICI therapy may need to be avoided in patients with type 1 DM. Further studies are required to evaluate the safety and efficacy of ICI therapy in patients with type 1 DM. If ICI therapy is started in advanced NSCLC patients with type 1 DM, it is important to observe patients in the hospital as well as in outpatient settings, including pharmacies.³⁴⁾

In our study, the presence of ADs was similarly associated with increased mortality in both advanced NSCLC patient populations of those who received ICI or conventional chemotherapy. While some studies have shown that the prognosis of AD patients is similar to that of non-AD patients, thus lacking conclusive evaluation, several other studies align with our findings. Specifically, studies have indicated worse survival outcomes for advanced NSCLC patients with RA or dermatomyositis/polymyositis treated with conventional chemotherapy.³⁵⁾ In addition, a study evaluating treatment, including ICI therapy, for advanced NSCLC patients with ADs have reported a trend toward poorer prognosis in these patients.¹⁷⁾ Thus, because the presence of AD may affect mortality in advanced NSCLC patients, analyses that compared survival between patients with and without ADs, particularly focusing on patients receiving ICI therapy, should be interpreted with caution.

Several limitations should be noted in our study. First, although the association between ICI therapy and OS in advanced NSCLC patients with ADs was observed, causality cannot be firmly established. While we adjusted for as many potential confounding factors as possible, factors such as performance status could not be included. However, even in the presence of unmeasured confounding factors, if both HRs of ICI therapy for patients with and without ADs are equally biased, the assertion of similar HRs for patients with and without ADs remains valid. Second, we were unable to collect data on the incidence of serious irAEs and a flare-up of their baseline pathological conditions. A recent systematic review on the use of ICIs in cancer patients with ADs suggested that these therapies can be safely managed without treatment interruption.³⁶⁾ In fact, our study showed no clear difference in the number of treatment cycles with ICIs between patients with ADs, except type 1 DM, and those without ADs. However, the statement regarding the overall effectiveness of ICI therapy for cancer patients with ADs could not be confirmed in our study. Third, we were unable to investigate how AD status affects outcomes. Patients with active ADs have been reported to have decreased survival compared to patients with inactive ADs.^10,37) Most patients with ADs in our study did not receive immunosuppressive drugs, and it is likely that many patients with stabilized ADs were incorporated into the study. Fewer patients with ADs under immunosuppression received ICI therapy than conventional chemotherapy, suggesting that patients with active ADs tend to avoid ICI therapy. Furthermore, due to the characteristics of the database, it is impossible to judge when AD has been diagnosed at another hospital, accurately calculating the months between the diagnosis of AD and the diagnosis of advanced NSCLC is not possible. If the disease duration of AD differs between patients with AD who received ICI or conventional chemotherapy, this may impact the prognosis of patients with advanced NSCLC.

CONCLUSION

The study suggested that ICI therapy was associated with reduced mortality in both groups of patients with advanced NSCLC, regardless of the presence of ADs, and these associations were comparable. However, for some specific ADs including type 1 DM, the results were inconclusive. It is crucial to consider treatment strategies for each type of ADs and engage in comprehensive discussions regarding the risk-benefit profile and ensure meticulous observation involving a multidisciplinary approach.

Conflict of Interest

Author YI, YN, YS, and AI declare they have no financial interests. KS received lecture fees from Eli Lilly Japan, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, and Kyowa Kirin. TI received lecture fees from JCR Pharmaceuticals and Kyowa Kirin. AS received lecture fees from AbbVie, AstraZeneca plc, Asahi Kasei Corporation, Astellas Pharma, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Janssen Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Mallinckrodt Pharmaceuticals, Maruho, Merck Biopharma, Mitsubishi Tanabe Pharma Corporation, Nipro Corporation, Nippon Shinyaku, Novo Nordisk Pharma, Ono Pharmaceutical, Pfizer, Shionogi Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical Company Limited, and Torii Pharmaceutical.

Supplementary Materials

This article contains supplementary materials.

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