Re: GLP-1 수용체 작용제 신장질환 효과 2022 jama!!

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Original Investigation 

Diabetes and Endocrinology

Association of Glucagon-Like Peptide-1 Receptor Agonist vs Dipeptidyl Peptidase-4 Inhibitor Use With Mortality Among Patients With Type 2 Diabetes and Advanced Chronic Kidney Disease

Jia-Jin Chen, MD1; Chao-Yi Wu, MD, PhD2; Chang-Chyi Jenq, MD1; et al

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JAMA Netw Open

Published Online: March 7, 2022

2022;5;(3):e221169. doi:10.1001/jamanetworkopen.2022.1169

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Key Points

Question  Is use of glucagon-like peptide-1 (GLP-1) receptor agonists among patients with diabetes and advanced-stage chronic kidney disease or end-stage kidney disease associated with better outcomes than use of dipeptidyl peptidase-4 (DPP-4) inhibitors?

Findings  This cohort study comprising 27 279 participants with type 2 diabetes and advanced-stage chronic kidney disease or end-stage kidney disease revealed that the use of GLP-1 receptor agonists was associated with lower all-cause mortality and lower sepsis- and infection-related mortality than was use of DPP-4 inhibitors.

Meaning  In this study, use of GLP-1 receptor agonists was associated with better outcomes compared with use of DPP-4 inhibitors among patients with type 2 diabetes and advanced-stage chronic kidney disease.

Abstract

Importance  Glucagon-like peptide-1 (GLP-1) receptor agonist use is associated with reduced mortality and improved cardiovascular outcomes in the general population with diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used antidiabetic agents for patients with advanced-stage chronic kidney disease (CKD). The association of these 2 drug classes with outcomes among patients with diabetes and advanced-stage CKD or end-stage kidney disease (ESKD) is not well understood.

Objective  To assess whether use of GLP-1 receptor agonists in a population with diabetes and advanced-stage CKD or ESKD is associated with better outcomes compared with use of DPP-4 inhibitors.

Design, Setting, and Participants  This retrospective cohort study used data on patients with type 2 diabetes and stage 5 CKD or ESKD obtained from the National Health Insurance Research Database of Taiwan. The study was conducted between January 1, 2012, and December 31, 2018. Data were analyzed from June 2020 to July 2021.

Exposures  Treatment with GLP-1 receptor agonists compared with treatment with DPP-4 inhibitors.

Main Outcomes and Measures  All-cause mortality, sepsis- and infection-related mortality, and mortality related to major adverse cardiovascular and cerebrovascular events were compared between patients treated with GLP-1 receptor agonists and patients treated with DPP-4 inhibitors. Propensity score weighting was used to mitigate the imbalance among covariates between the groups.

Results  Of 27 279 patients included in the study, 26 578 were in the DPP-4 inhibitor group (14 443 [54.34%] male; mean [SD] age, 65 [13] years) and 701 in the GLP-1 receptor agonist group (346 [49.36%] male; mean [SD] age, 59 [13] years). After weighting, the use of GLP-1 receptor agonists was associated with lower all-cause mortality (hazard ratio [HR], 0.79; 95% CI, 0.63-0.98) and lower sepsis- and infection-related mortality (HR, 0.61; 95% CI, 0.40-0.91). Subgroup analysis demonstrated a lower risk of mortality associated with use of GLP-1 receptor agonists compared with DDP-4 inhibitors among patients with cerebrovascular disease (HR, 0.33; 95% CI, 0.12-0.86) than among those without cerebrovascular disease (HR, 0.89; 95% CI, 0.71-1.12) (P = .04 for interaction).

Conclusions and Relevance  Treatment with GLP-1 receptor agonists was associated with lower all-cause mortality among patients with type 2 diabetes, advanced-stage CKD, and ESKD than was treatment with DPP-4 inhibitors. Additional well-designed, prospective studies are needed to confirm‎ the potential benefit of GLP-1 receptor agonist treatment for patients with advanced CKD or ESKD.

핵심 포인트

질문

당뇨병과 만성 신장 질환 후기 단계 또는 말기 신장 질환을 가진 환자에서 글루카곤 유사 펩티드-1 (GLP-1) 수용체 작용제의 사용이 디펩티딜 펩티다제-4 (DPP-4) 억제제의 사용보다 더 나은 결과를 보였나요?

결과

제2형 당뇨병과 만성 신장 질환 후기 단계 또는 말기 신장 질환을 가진 27,279명의 참가자를 대상으로 한 이 코호트 연구에서, GLP-1 수용체 작용제의 사용은 DPP-4 억제제 사용에 비해 전체 사망률 및 패혈증 및 감염 관련 사망률이 더 낮았다는 것이 밝혀졌습니다.

의의

이 연구에서 제2형 당뇨병과 만성 신장 질환 말기 환자에게서 GLP-1 수용체 작용제 사용은 DPP-4 억제제 사용에 비해 더 나은 결과를 보였습니다.

초록

중요성 글루카곤 유사 펩티드-1 (GLP-1) 수용체 작용제 사용은 당뇨병을 가진 일반 인구에서 사망률 감소 및 심혈관 결과 개선과 연관되어 있습니다. 디펩티딜펩티다제-4 (DPP-4) 억제제는 만성 신장 질환 (CKD) 후기 단계 환자에서 일반적으로 사용되는 항당뇨병제입니다. (CKD)에서 널리 사용됩니다. 이 두 약물 군이 당뇨병과 말기 CKD 또는 말기 신장 질환(ESKD)을 동반한 환자에서의 결과와의 연관성은 잘 알려져 있지 않습니다.

목적 당뇨병과 말기 CKD 또는 ESKD를 동반한 인구에서 GLP-1 수용체 작용제 사용이 DPP-4 억제제 사용과 비교하여 더 나은 결과를 보였는지 평가하는 것입니다.

연구 설계, 환경, 및 대상자 이 후향적 코호트 연구는 대만 국민건강보험 연구 데이터베이스에서 수집된 제2형 당뇨병 및 CKD 5단계 또는 ESKD 환자의 데이터를 사용했습니다. 연구는 2012년 1월 1일부터 2018년 12월 31일까지 진행되었습니다. 데이터는 2020년 6월부터 2021년 7월까지 분석되었습니다.

노출 GLP-1 수용체 작용제 치료와 DPP-4 억제제 치료를 비교했습니다.

주요 결과 및 측정 항목 전체 사망률, 패혈증 및 감염 관련 사망률, 주요 심혈관 및 뇌혈관 사건 관련 사망률을 GLP-1 수용체 작용제 치료군과 DPP-4 억제제 치료군 간에 비교했습니다. 그룹 간 공변량 불균형을 완화하기 위해 경향 점수 가중치를 적용했습니다.

결과 연구에 포함된 27,279명의 환자 중

26,578명은 DPP-4 억제제 그룹에 (남성 14,443명 [54.34%]; 평균 [표준편차] 연령, 65 [13] 세)이며,

GLP-1 수용체 작용제 그룹에는 701명(남성 346명 [49.36%]; 평균 [표준편차] 연령, 59 [13] 세)이 포함되었습니다.

체중 조정 후,

GLP-1 수용체 작용제 사용은 전체 사망률 감소와 연관되었습니다 (위험비 [HR], 0.79; 95% 신뢰구간, 0.63-0.98) 및 패혈증 및 감염 관련 사망률(HR, 0.61; 95% 신뢰구간, 0.40-0.91)이 낮았습니다.

하위군 분석 결과, 뇌혈관 질환이 있는 환자에서 GLP-1 수용체 작용제 사용은 DDP-4 억제제 사용에 비해 사망 위험이 낮았으며 (HR, 0.33; 95% 신뢰구간, 0.12-0.86)이 뇌혈관 질환이 없는 환자(HR, 0.89; 95% 신뢰구간, 0.71-1.12)보다 낮았습니다 (P = 0.04 상호작용).

결론 및 의미

GLP-1 수용체 작용제 치료는

제2형 당뇨병, 말기 신장 질환(CKD), 말기 신부전(ESKD) 환자에서

DPP-4 억제제 치료에 비해 전체 사망률이 낮았습니다.

말기 CKD 또는 ESKD 환자에서

GLP-1 수용체 작용제 치료의 잠재적 이점을 확인하기 위해

추가로 잘 설계된 전향적 연구가 필요합니다.

Introduction

Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are contributors to the health burden and are associated with increased mortality and cardiovascular events.1,2 Type 2 diabetes is the most common cause of CKD, and both diabetes and CKD are associated with increased all-cause mortality and increased rates of infection and cardiovascular events.3,4 The high mortality among patients with diabetes and CKD or ESKD is mostly attributable to cardiovascular or infection-related events.5,6 Both glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are associated with better blood glucose control, greater body weight reduction, lower mortality, and lower incidence of cardiovascular events in the general population with diabetes.7-9 According to the American Diabetes Association guideline,10 GLP-1 receptor agonist treatment is recommended for patients with diabetes and CKD who have an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 and are at risk for cardiovascular disease. According to the Kidney Disease: Improving Global Outcomes 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease,11,12 GLP-1 receptor agonist treatment is suggested for individuals who are unable to use metformin or SGLT-2 inhibitors. Unlike SGLT-2 inhibitors, GLP-1 receptor agonists can be used in patients with advanced-stage CKD or ESKD. A recent network meta-analysis7 demonstrated potentially different clinical outcomes after use of GLP-1 receptor agonists and use of dipeptidyl peptidase-4 (DPP-4) inhibitors in the general population with diabetes. In that study, use of GLP-1 receptor agonists was associated with improved survival compared with use of DPP-4 inhibitors.

However, randomized clinical trials have usually excluded or enrolled small numbers of patients with advanced-stage CKD or ESKD.13,14 Meanwhile, DPP-4 inhibitors are commonly prescribed to patients with advanced-stage CKD or ESKD owing to their safety profiles and effectiveness for glucose control15 despite the neutral effect on the kidneys and cardiovascular outcomes.15 However, the association of GLP-1 receptor agonist treatment with improved survival has been discussed less frequently for patients with advanced CKD or ESKD. Furthermore, to our knowledge, there have been no real-world studies comparing GLP-1 receptor agonists with DPP-4 inhibitors for treatment of patients with advanced-stage CKD or ESKD. In this study, we aimed to assess whether use of GLP-1 receptor agonists among patients with type 2 diabetes and stage 5 CKD or ESKD was associated with better outcomes compared with use of DPP-4 inhibitors.

소개

만성 신장 질환(CKD) 및 말기 신장 질환(ESKD)은 건강에 대한 부담의 원인이 되며, 사망률 및 심혈관 질환의 발생률 증가와 관련이 있습니다.1,2 제 2형 당뇨병은 CKD의 가장 흔한 원인이며, 당뇨병과 CKD는 모두 모든 원인으로 인한 사망률의 증가 및 감염 및 심혈관 질환의 발생률 증가와 관련이 있습니다.3,4

당뇨병과 CKD 또는 ESKD를 가진 환자의 높은 사망률은

주로 심혈관 또는 감염 관련 사건에 기인합니다.5,6

글루카곤 유사 펩티드-1(GLP-1) 수용체 작용제와

나트륨-글루코스 공수송체-2(SGLT-2) 억제제는

당뇨병을 가진 일반 인구에서 혈당 조절 개선, 체중 감소, 사망률 감소, 심혈관 사건 발생률 감소와 연관되어 있습니다.7-9

미국 당뇨병 협회 지침에 따르면,10

GLP-1 수용체 작용제 치료는

추정 사구체 여과율(eGFR)이 60 mL/min/1.73 m2 미만이며

심혈관 질환 위험이 있는 당뇨병 및 CKD 환자에게 권장됩니다.

신장 질환: Improving Global Outcomes 2020 만성 신장 질환 환자의 당뇨병 관리 임상 실무 지침,11,12에 따르면, 메트포르민이나 SGLT-2 억제제를 사용할 수 없는 개인에게는 GLP-1 수용체 작용제 치료가 권장됩니다.

SGLT-2 억제제와 달리 GLP-1 수용체 작용제는 말기 CKD 또는 말기 신부전(ESKD) 환자에게도 사용할 수 있습니다.

최근 네트워크 메타-분석7은 당뇨병을 가진 일반 인구에서 GLP-1 수용체 작용제와 디펩티딜펩티다제-4 (DPP-4) 억제제 사용 후 잠재적으로 다른 임상 결과를 보여주었습니다. 해당 연구에서 GLP-1 수용체 작용제 사용은 DPP-4 억제제 사용에 비해 생존율 개선과 연관되었습니다.

그러나 무작위 임상 시험은 일반적으로 말기 CKD 또는 ESKD 환자를 배제하거나 소수만 포함시켰습니다.13,14 한편, DPP-4 억제제는 신장 및 심혈관 결과에 대한 중립적 효과에도 불구하고 혈당 조절에 대한 안전성 프로파일과 효과로 인해 말기 CKD 또는 ESKD 환자에게 일반적으로 처방됩니다.15 그러나 GLP-1 수용체 작용제 치료와 생존율 개선 간의 연관성은 진행성 CKD 또는 ESKD 환자에게서 덜 자주 논의되었습니다. 또한, 우리 지식 범위 내에서 진행성 CKD 또는 ESKD 환자의 치료를 위해 GLP-1 수용체 작용제와 DPP-4 억제제를 비교한 실제 임상 연구는 없습니다. 본 연구에서는 제2형 당뇨병과 5단계 CKD 또는 ESKD를 가진 환자에서 GLP-1 수용체 작용제 사용이 DPP-4 억제제 사용과 비교해 더 나은 결과를 보였는지 평가하는 것을 목표로 했습니다.

Methods

Data Source

This retrospective cohort study was built on data from the National Health Insurance Research Database (NHIRD) in Taiwan. Taiwan’s national health insurance system is a mandatory national health insurance program that covers more than 99.9% of Taiwan’s population. The NHIRD data sets contain deidentified information such as age, sex, examinations, medications, interventions, surgeries, admissions, and outpatient clinics. Diseases and outcomes were identified in the NHIRD using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Detailed information regarding the national health insurance system as a reliable source for real-world studies has been demonstrated previously.16-18 This study was approved by the institutional review board of the Chang Gung Memorial Hospital. The need for individual informed consent was waived by the institutional review board of Chang Gung Memorial Hospital because personal identification data were not included in the NHIRD. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and the RECORD-PE guideline.19

Study Population

This study included data for patients with type 2 diabetes and stage 5 CKD or ESKD obtained from January 1, 2012, to December 31, 2018. Stage 5 CKD was identified using a combination of ICD-9-CM (016.0, 042, 095.4, 189, 223, 236.9, 250.4, 271.4, 274.1, 403-404, 440.1, 442.1, 446.21, 447.3, 572.4, 580-589, 590-591, 593, 642.1, 646.2, 753, and 984) and ICD-10 (B20, A52.75, C64-68, D30, D41, E11.29, E74.8, M10.30, N20, I70.1, I72.2, M31, I77.3, K76.7, N00-08, N10-15, N18, N28.83, N28.81, N28.1, N28.9, O10.41-43, O12.14, O26.831-839, and Q60-4) codes and a prescription for erythropoiesis-stimulating agents. End-stage kidney disease requiring dialysis was verified by identifying insured individuals who had a diagnostic code for ESKD (either ICD-9-CM code 585 or ICD-10 code N186) and received an appropriate catastrophic illness certificate for maintenance dialysis. Patients who were first prescribed either a GLP-1 receptor agonist or a DPP-4 inhibitor 3 months before the index date were included. The index date was defined as 91 days after the first exposure to a GLP-1 receptor agonist or DPP-4 inhibitor. We excluded patients who had incomplete data, were younger than 20 years, had major adverse cardiovascular and cerebrovascular events (MACCE) 90 days before the index date, had a malignant neoplasm detected, or underwent a kidney transplant or dialysis or died 90 days before the index date (Figure). We divided the eligible patients into 2 groups based on the use of GLP-1 receptor agonists or DPP-4 inhibitors during the 3-month exposure window.

Figure.  Flowchart of Patient Enrollment

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CKD-5 indicates stage 5 chronic kidney disease; DPP-4 inhibitor, dipeptidyl peptidase 4 inhibitor; ESKD, end-stage kidney disease; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MACCE, major adverse cardiovascular or cerebrovascular event.

Covariates

Age, sex, area of residence (urban or rural area), income level, occupation, and 10 comorbidities (hypertension, dyslipidemia, cirrhosis, systemic lupus erythematosus, atrial fibrillation, peripheral arterial disease, coronary artery disease or ischemic heart disease, heart failure, cerebrovascular disease, and ESKD requiring dialysis) were used as covariates (eTable 1 in the Supplement). Overall health was measured using the Charlson Comorbidity Index.20 The baseline characteristics of the patients were identified before the index date to track any history of major comorbidities from the NHIRD. Comorbidities were defined as at least 1 inpatient diagnosis or 2 outpatient diagnoses of a given disease within 1 year before the index date. Medications were also eval‎uated by review of prescription records in the NHIRD. The following medications listed in prescription records within 90 days before the index date were extracted: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, aspirin, diuretics, fibrate, gemfibrozil, nonsteroidal anti-inflammatory drugs, or other types of antidiabetic medications (sulfonylurea, α-glucosidase inhibitors, insulin, and meglitinide analogs).

Outcome Measurement

The primary outcome was all-cause mortality after the index date during the follow-up period. The secondary outcomes were sepsis- or infection-related mortality and MACCE-related mortality. MACCE included myocardial infarction, cardiogenic shock, heart failure, coronary revascularization, coronary artery bypass surgery, thrombolysis therapy, malignant arrhythmia, and stroke (eTable 1 in the Supplement). MACCE-related mortality was identified by the discharge death code (ICD-9-CM: 390-392, 393-398, 410-414, 420-429, 430-438, and 440; ICD-10: I10-15, I01-02, I05-09, I20-25, I27, I30-52, I60-69, and I70-71) or in-hospital mortality with a diagnostic code for a MACCE21 ,22 (eTable 1 in the Supplement). Infection- and sepsis-related mortality was also identified using the discharge death code (ICD-9-CM: 010-016, 033, 036-038, 320-322, 480-487, and 490-493; ICD-10: A15-19, A40-41, G00, G03, and J10-J18) or in-hospital mortality with the diagnostic code for infection or sepsis (eTable 1 in the Supplement). All patients were monitored until death or December 31, 2018. For survival analysis, the follow-up period was 4 years.

Statistical Analysis

To reduce confounding and selection bias, the propensity score weighting method was used to balance covariates between the 2 groups; these included baseline characteristics, comorbidities, antidiabetic agents, antihypertensive agents, ESKD requiring dialysis, and Charlson Comorbidity Index score. The absolute standardized mean difference was used as a metric of propensity score performance for both GLP-1 receptor agonists and DPP-4 inhibitors.23 Absolute standardized mean difference values that were higher than 0.1 indicated an imbalance between groups.23 The incidence of the outcome of interest was computed as the total study outcomes during the follow-up period divided by person-years at risk. The hazard ratio (HR) with 95% CI of each outcome was estimated using a Cox proportional hazards regression model. The event-free survival rate among patients treated with GLP-1 receptor agonists vs DPP-4 inhibitors was eval‎uated using the Kaplan-Meier method, and a P value of survival analysis was calculated by log-rank test. For the survival analysis, follow-up duration was estimated from the index date to first outcome event diagnosis (all-cause mortality, MACCE-related mortality, or sepsis-related mortality, defined by the date of health insurance policy termination) or until December 31, 2018, for uncensored participants and the end of the 4-year follow-up period for those who were censored. For MACCE-related mortality and sepsis-related mortality, participants with health insurance policy termination (mostly because of death) owing to other causes of death were censored.

Subgroup analysis was conducted to explore potential different treatment effects between subgroups by age (<65 years or ≥65 years), sex, diagnosis of coronary artery disease or ischemic heart disease, diagnosis of cerebrovascular disease, and use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and ESKD requiring dialysis. In subgroup analysis, the Cox proportional hazards regression model and subgroup-specific HRs were used to estimate subgroup-specific mean treatment effect. Comparison between subgroups was performed after independent inverse probability of treatment weighting adjustment for covariates (atrial fibrillation, congestive heart failure, hypertension, cirrhosis, peripheral arterial disease, systemic lupus erythematosus, dyslipidemia, and use of prescription drugs) and unselected subgroup specific covariates. Results of subgroup analysis were shown using a forest plot (eFigure 2 in the Supplement). Sensitivity analyses were also conducted to exclude (1) participants with a history of switching between GLP-1 receptor agonists and DPP-4 inhibitors and (2) those who were outliers in the propensity score–matched analysis. Data were analyzed from June 2020 to July 2021. Statistical significance was defined at 2-sided P < .05. All statistical analyses were conducted using SAS, version 9.4 (SAS Institute).

Results

Patient Characteristics

A total of 75 556 patients with type 2 diabetes and stage 5 CKD or ESKD who were receiving dialysis were identified between January 1, 2012, and December 31, 2018. A total of 48 277 patients were excluded because they did not use target medications (n = 40 428) or fulfilled the exclusion criteria (incomplete data [n = 1479], diagnosis of diabetes after enrollment [n = 182], <20 years of age [n = 14], malignant neoplasm [n = 2815]; kidney transplant [n = 255]; and diagnosis of MACCE, receipt of dialysis, or death before the index date [n = 3104]) (Figure). Of 27 279 patients included in the study, 26 578 were in the DPP-4 inhibitor group (14 443 [54.34%] male; mean [SD] age, 65 [13] years) and 701 in the GLP-1 receptor agonist group (346 [49.36%] male; mean [SD] age, 59 [13] years). Baseline demographic characteristics, comorbidities, and medications prescribed for the 2 groups are summarized in Table 1. Before propensity score weighting, the DPP-4 inhibitor group was older, concentrated in rural areas, and included fewer patients receiving dialysis and more patients receiving an angiotensin-converting enzyme inhibitor, diuretics, and insulin compared with the GLP-1 receptor agonist group. After propensity score weighting, all analyzed covariates were balanced between the 2 groups. After propensity score weighting, the DPP-4 inhibitor group consisted of 26 568 patients, and the GLP-1 receptor agonist group consisted of 603 patients. The mean (SD) age was 66 (13) years in the DPP-4 inhibitor group and 65 (11) years in the GLP-1 receptor agonist group. In the DPP-4 inhibitor group, 14 414 patients (54.25%) were male, and in the GLP-1 receptor agonist group, 319 (52.90%)were male. Hypertension was the most common comorbidity in the enrolled population; after propensity score weighting, 22 369 patients (84.20%) in the DPP-4 inhibitor group and 506 (83.92%) in the GLP-1 receptor agonist group had hypertension. The mirrored histogram of propensity score distribution showed substantial overlap of propensity scores between the 2 groups. For primary and second outcomes, the median follow-up duration was 3.57 years (IQR, 1.95-4.00 years) in the DPP-4 inhibitor group and 1.76 years (IQR, 1.03-3.89 years) in the GLP-1 receptor agonist group.

환자 특성

2012년 1월 1일부터 2018년 12월 31일까지 제2형 당뇨병과 5단계 만성 신장 질환(CKD) 또는 말기 신부전(ESKD)을 진단받고 투석 치료를 받은 환자 75,556명이 식별되었습니다. 총 48,277명의 환자가 대상 약물을 사용하지 않았기 때문에(n = 40,428) 또는 배제 기준을 충족했기 때문에(데이터 불완전[n = 1,479], 등록 후 당뇨병 진단[n = 182], 20세 미만[n = 14], 악성 종양[n = 2,815]; 신장 이식 [n=255]; 및 MACCE 진단, 투석 치료, 또는 지표일 이전 사망 [n=3,104])(그림).

연구에 포함된 27,279명의 환자 중 26,578명이 DPP-4 억제제 그룹에 속했으며(남성 14,443명 [54.34%]; 평균 [표준편차] 연령, 65 [13]세)이며, GLP-1 수용체 작용제 그룹은 701명(남성 346명 [49.36%]; 평균 [표준편차] 연령, 59 [13]세)이었습니다. 두 그룹의 기저 인구통계학적 특성, 동반 질환, 처방된 약물은 표 1에 요약되어 있습니다. 경향 점수 가중치 적용 전, DPP-4 억제제 그룹은 GLP-1 수용체 작용제 그룹보다 연령이 높았고, 농촌 지역에 집중되어 있었으며, 투석 치료를 받는 환자가 적고, 안지오텐신 전환 효소 억제제, 이뇨제, 인슐린을 투여받은 환자가 더 많았습니다.-4 억제제 그룹은 연령이 더 높았고, 농촌 지역에 집중되어 있었으며, 투석 치료를 받는 환자가 적고, 안지오텐신 전환 효소 억제제, 이뇨제, 인슐린을 투여받는 환자가 더 많았습니다. 경향 점수 가중치 조정 후, 분석된 모든 공변량은 두 그룹 간 균형이 맞았습니다. 경향 점수 가중치 조정 후, DPP-4 억제제 그룹은 26,568명의 환자로 구성되었으며, GLP-1 수용체 작용제 그룹은 603명의 환자로 구성되었습니다. 평균(표준편차) 연령은 DPP-4 억제제 그룹에서 66(13)세, GLP-1 수용체 작용제 그룹에서 65(11)세였습니다. DPP-4 억제제 그룹에서는 14,414명(54.25%)이 남성이었고, GLP-1 수용체 작용제 그룹에서는 319 (52.90%)가 남성입니다. 고혈압은 등록된 인구에서 가장 흔한 동반 질환이었습니다; 경향성 점수 가중 후 DPP-4 억제제 그룹에서 22,369명(84.20%)이 고혈압을 가지고 있었고, GLP-1 수용체 작용제 그룹에서는 506명(83.92%)이 고혈압을 가지고 있었습니다. 경향성 점수 분포의 거울 히스토그램은 두 그룹 간 경향성 점수의 상당한 중첩을 보여주었습니다. 주요 및 부차적 결과에 대한 중간 추적 관찰 기간은 DPP-4 억제제 그룹에서 3.57년 (IQR, 1.95-4.00년)이었으며, GLP-1 수용체 작용제 그룹에서는 1.76년 (IQR, 1.03-3.89년)이었습니다.

Table 1.  Baseline Characteristics of Patients With Diabetes and Stage 5 Chronic Kidney Disease or End-Stage Kidney Disease

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CharacteristicBefore propensity score weightingAfter propensity score weightingPatients, No. (%)ASMDPatients, No. (%)ASMDDPP-4 inhibitor (n = 26 578)GLP-1 receptor agonist (n = 701)DPP-4 inhibitor (n = 26 568)GLP-1 receptor agonist (n = 603)

Age, mean (SD)	65 (13)	59 (13)	0.470	66 (13)	65 (11)	0.029
Sex
Female	12 135 (46.66)	355 (50.64)	0.100	12 154 (45.75)	284 (47.10)	0.027
Male	14 443 (54.34)	346 (49.36)		14 414 (54.25)	319 (52.90)
Area of residence
Urban	6584 (24.77)	260 (29.39)	0.140	6605 (24.86)	155 (25.70)	0.028
Suburban	7440 (27.99)	219 (31.24)		7455 (28.06)	161 (26.67)
Rural	12 554 (47.23)	276 (39.37)		12 509 (47.08)	287 (47.64)
Occupation
Dependent	10 276 (38.66)	242 (34.52)	0.210	10 244 (38.56)	232 (38.42)	0.038
Civil servant	282 (1.06)	11 (1.57)		284 (1.07)	7 (1.15)
Nonmanual worker	2109 (7.94)	100 (14.27)		2146 (8.08)	55 (9.09)
Manual worker	8932 (33.61)	222 (31.67)		8921 (33.58)	204 (33.86)
Other	4979 (18.73)	126 (17.97)		4974 (18.72)	105 (17.49)
Comorbidities
Hypertension	22 388 (84.24)	579 (82.60)	0.044	22 369 (84.20)	506 (83.92)	0.007
Dyslipidemia	11 990 (45.11)	348 (49.64)	0.091	12 010 (45.20)	284 (47.07)	0.038
Cirrhosis	634 (2.39)	17 (2.43)	0.003	632 (2.38)	14 (2.39)	<0.001
SLE	47 (0.18)	4 (0.57)	0.065	48 (0.18)	1 (0.17)	0.026
Atrial fibrillation	561 (2.11)	9 (1.28)	0.064	558 (2.10)	10 (1.70)	0.029
Peripheral arterial disease	1231 (4.63)	36 (5.14)	0.023	1230 (4.63)	30 (4.97)	0.016
Coronary artery disease/ischemic heart disease	5566 (20.94)	156 (22.25)	0.032	5567 (20.95)	122 (20.19)	0.019
Heart failure	4631 (17.42)	120 (17.12)	0.008	4624 (17.40)	120 (19.84)	0.063
Cerebrovascular disease	3311 (12.46)	76 (10.84)	0.050	3302 (12.43)	68 (11.29)	0.035
Dialysis	5819 (21.89)	208 (29.67)	0.180	5862 (22.06)	136 (22.53)	0.011
Charlson Comorbidity Index score, mean (SD)	2.98 (1.49)	2.90 (1.41)	0.059	2.98 (1.49)	2.90 (1.31)	0.062
Medications
ACEI	2864 (10.78)	41 (5.85)	0.180	2835 (10.67)	56 (9.24)	0.048
ARB	16 216 (61.01)	449 (64.05)	0.063	16 220 (61.05)	380 (62.93)	0.039
Aspirin	7898 (29.72)	246 (35.09)	0.120	7922 (29.82)	190 (31.54)	0.037
β-Blocker	8745 (32.90)	261 (37.23)	0.091	8760 (32.97)	196 (32.47)	0.011
CCB	18 999 (71.48)	482 (68.76)	0.060	18 977 (71.43)	423 (70.05)	0.030
Diuretic	14 826 (55.78)	340 (48.50)	0.150	14 783 (55.64)	320 (53.09)	0.051
Fibrate	1910 (7.19)	90 (12.84)	0.190	1941 (7.31)	44 (7.33)	<0.001
Gemfibrozil	572 (2.15)	21 (3.00)	0.053	577 (2.17)	11 (1.80)	0.026
NSAID	8381 (31.53)	207 (29.53)	0.044	8371 (31.51)	179 (29.60)	0.042
Sulfonylurea	12 004 (45.17)	311 (44.37)	0.016	11 999 (45.16)	254 (42.14)	0.061
Acarbose	3730 (14.03)	109 (15.55)	0.043	3730 (14.04)	84 (13.98)	0.002
Insulin	7813 (29.40)	114 (16.26)	0.320	7732 (29.10)	164 (27.13)	0.044
Meglitinide	6911 (26.00)	168 (23.97)	0.047	6899 (25.97)	143 (23.71)	0.052

Primary and Secondary Outcomes

The rates of all-cause mortality, sepsis- or infection-related mortality, and MACCE-related mortality in the 2 study groups are shown in Table 2. The rate of all-cause mortality was 7.95 per 100 person-years (95% CI, 7.76-8.15 per 100 person-years) in the DPP-4 inhibitor group and 6.10 per 100 person-years (95% CI, 4.76-7.45 per 100 person-years) in the GLP-1 receptor agonist group. After propensity score weighting, use of GLP-1 receptor agonists was associated with lower all-cause mortality compared with use of DPP-4 inhibitors (HR, 0.79; 95% CI, 0.63-0.98; P = .03). The rate of sepsis- or infection-related mortality was 3.01 per 100 person-years (95% CI, 2.88-3.13 per 100 person-years) in the DPP-4 inhibitor group and 1.80 per 100 person-years (95% CI, 1.07-2.53 per 100 person-years) in the GLP-1 receptor agonist group. There was a lower risk for sepsis- or infection-related mortality in the GLP-1 receptor agonist group vs the DPP-4 inhibitor group was (HR, 0.61; 95% CI, 0.40-0.91; P = .02). The rate of MACCE-related mortality was 2.56 per 100 person-years (95% CI, 2.45-2.67 per 100 person-years) in the DPP-4 inhibitor group and 2.64 per 100 person-years (95% CI, 1.75-3.53 per 100 person-years) in the GLP-1 receptor agonist group. MACCE-related mortality in the GLP-1 receptor agonist group was similar to that in the DPP-4 inhibitor group (HR, 1.07; 95% CI, 0.76-1.51; P = .69) (Table 2). The survival curve analysis for all-cause mortality, sepsis- and infection-related mortality, and MACCE-related mortality after propensity score weighting is provided in eFigure 1 in the Supplement.

2개 연구 그룹의 모든 원인으로 인한 사망률, 패혈증 또는 감염 관련 사망률, MACCE 관련 사망률은 표 2에 표시되어 있습니다. 전체 사망률은 DPP-4 억제제 그룹에서 100 인년당 7.95 (95% 신뢰구간, 7.76-8.15 per 100 인년)였으며, GLP-1 수용체 작용제 그룹에서는 100 인년당 6.10 (95% 신뢰구간, 4.76-7.45 per 100 인년-년)였습니다. 경향 점수 가중 후, GLP-1 수용체 작용제 사용은 DPP-4 억제제 사용에 비해 전체 사망률이 낮았으며(HR, 0.79; 95% CI, 0.63-0.98; P = 0.03). 세균성 패혈증 또는 감염 관련 사망률은 DPP-4 억제제 그룹에서 100 인년당 3.01 (95% 신뢰구간, 2.88-3.13 per 100 인년)이었으며, GLP-1 수용체 작용제 그룹에서는 1.80 per 100 인년(95% CI, 1.07-2.53 per 100 인년)이었습니다. GLP-1 수용체 작용제 그룹은 DPP-4 억제제 그룹에 비해 패혈증 또는 감염 관련 사망 위험이 낮았으며 (위험비, 0.61; 95% 신뢰구간, 0.40-0.91; P = 0.02). DPP-4 억제제 그룹에서 MACCE 관련 사망률은 100인년당 2.56 (95% 신뢰구간, 2.45-2.67)이었으며, GLP-1 수용체 작용제 그룹에서는 100인년당 2.64 (95% 신뢰구간, 1.75-3.53명/100인년)이었습니다. GLP-1 수용체 작용제 그룹의 MACCE 관련 사망률은 DPP-4 억제제 그룹과 유사했습니다(HR, 1.07; 95% CI, 0.76-1.51; P = 0.69) (표 2). 경향 점수 가중치를 적용한 전체 사망률, 패혈증 및 감염 관련 사망률, MACCE 관련 사망률의 생존 곡선 분석은 보충 자료의 eFigure 1에 제공됩니다.

Table 2.  Analysis of Primary and Secondary Outcomes

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Event typeDPP-4 inhibitorsGLP-1 receptor agonistsGLP-1 receptor agonists vs DPP-4 inhibitorsEvents, No.aRate, per 100 person-years (95% CI)Events, No.bRate, per 100 person-years (95% CI)Hazard ratio (95% CI)P value

Before propensity score weighting
MACCE-related mortality	2009	2.57 (2.46-2.68)	39	2.60 (1.78-3.42)	1.05 (0.77-1.44)	.76
Sepsis- and infection-related mortality	2366	3.03 (2.91-3.15)	24	1.60 (0.96-2.24)	0.54 (0.36-0.80)	.003
All-cause mortality	6252	8.00 (7.80-8.20)	81	5.40 (4.23-6.58)	0.69 (0.56-0.86)	.001
After propensity score weighting
MACCE-related mortality	1999	2.56 (2.45-2.67)	34	2.64 (1.75-3.53)	1.07 (0.76-1.51)	.69
Sepsis- and infection-related mortality	2347	3.01 (2.88-3.13)	23	1.80 (1.07-2.53)	0.61 (0.40-0.91)	.02
All-cause mortality	6212	7.95 (7.76-8.15)	79	6.10 (4.76-7.45)	0.79 (0.63-0.98)	.03

Subgroup Analysis and Sensitivity Analysis

eFigure 2 in the Supplement presents the results of the subgroup analysis. A difference in all-cause mortality was identified between the use of GLP-1 receptor agonists and use of DDP-4 inhibitors among participants with and without cerebrovascular disease. Among participants with cerebrovascular disease, there was lower risk for all-cause mortality in the GLP-1 receptor group than in the DDP-4 inhibitor group (HR, 0.33; 95% CI, 0.12-0.86). This association was not observed among individuals without cerebrovascular disease (HR, 0.89; 95% CI, 0.71-1.12) (P = .04 for interaction). For MACCE-related mortality and for sepsis- and infection-related mortality, no significant treatment effect heterogeneity was detected.

Some enrolled participants switched from the GLP-1 receptor agonist group to the DDP-4 inhibitor group after the first GLP-1 receptor agonist prescription. We conducted sensitivity analysis to exclude these patients with a history of drug switching, and the results are presented as eTable 2 in the Supplement. Outliers in the propensity score–weighted analysis were included in further sensitivity analysis, and the results are shown in eTables 3 and 4 in the Supplement. The aforementioned lower all-cause and sepsis-related mortality associated with GLP-1 receptor agonist treatment compared with DPP-4 inhibitor treatment did not differ in each sensitivity analysis.

뇌혈관 질환이 있는 참가자와 없는 참가자 사이에서 GLP-1 수용체 작용제 사용과 DDP-4 억제제 사용 사이에 전체 사망률의 차이가 확인되었습니다. 뇌혈관 질환이 있는 참가자 중에서는 GLP-1 수용체 그룹이 DDP-4 억제제 그룹보다 전체 사망 위험이 낮았습니다 (HR, 0.33; 95% CI, 0.12-0.86). 이 연관성은 뇌혈관 질환이 없는 참가자에서는 관찰되지 않았습니다(HR, 0.89; 95% CI, 0.71-1.12) (P = .04 상호작용). MACCE 관련 사망률 및 세균성 감염 관련 사망률에서는 치료 효과 이질성이 유의미하게 관찰되지 않았습니다.

일부 등록 참가자는 첫 번째 GLP-1 수용체 작용제 처방 후 DDP-4 억제제 그룹으로 전환했습니다. 약물 전환 이력이 있는 환자를 제외하기 위해 감수성 분석을 수행했으며, 결과는 보충 자료의 eTable 2에 제시되었습니다. 경향 점수 가중 분석의 아웃라이어는 추가 감수성 분석에 포함되었으며, 결과는 보충 자료의 eTables 3 및 4에 표시되었습니다. 앞서 언급된 GLP-1 수용체 작용제 치료와 DPP-4 억제제 치료 간의 전체 사망률 및 패혈증 관련 사망률 감소는 각 감수성 분석에서 차이가 없었습니다.

Discussion

The 2 major findings of this study can be summarized as follows: (1) use of GLP-1 receptor agonists in patients with diabetes and stage 5 CKD or EKSD was associated with lower all-cause mortality compared with use of DPP-4 inhibitors and (2) use of GLP-1 receptor agonists was associated with lower sepsis- and infection-related mortality compared with use of DPP-4 inhibitors. A previous study reported that use of GLP-1 receptor agonists was associated with lower all-cause mortality, cardiovascular-related mortality, and kidney failure compared with placebo in the general population with diabetes.7 In that study, use of GLP-1 receptor agonists was also associated with improved outcomes compared with several traditional antidiabetic agents, including sulfonylureas, DPP-4 inhibitors, and thiazolidinedione. Nevertheless, the proportions of participants with advanced-stage CKD in large randomized clinical trials (Liraglutide Effect and Action in Diabetes: Eval‎uation of Cardiovascular Outcome Results [LEADER] trial13 and Researching Cardiovascular Events With a Weekly Incretin in Diabetes [REWIND] trial14) examining the clinical effects of GLP-1 receptor agonists were small despite enrollment of these patients in the trials. Real-world evidence regarding use of treatment with GLP-1 receptor agonists among patients with diabetes and late-stage CKD or ESKD is lacking. The lower all-cause mortality in the GLP-1 receptor agonist group compared with the DPP-4 inhibitor group among patients with diabetes and advanced-stage CKD or ESKD in our study is in agreement with the findings of Palmer et al.7

The difference between DPP-4 inhibitors and GLP-1 receptor agonists has been studied previously.7 ,24-43 Both drugs are based on the incretin pathway; however, DPP-4 inhibitors and GLP-1 receptor agonists showed different clinical efficacy.25 -43 Lower hemoglobin A1c levels,24 -34 greater body weight reduction,25 -27,31-33,35-40 improved β-cell function,25 ,26,28,33,36 improved cardiac function,27 ,41,42 and reduced albumin level27 ,42,43 were observed in randomized clinical trials comparing GLP-1 receptor agonists with DPP-4 inhibitors. The different clinical benefits (ie, better glucose control, metabolic benefit) between GLP-1 receptor agonists and DPP-4 inhibitors might explain the better outcomes observed in patients treated with GLP-1 receptor agonists than in those treated with DPP-4 inhibitors.7 These differences are summarized in eTable 5 in the Supplement.

Increased susceptibility to sepsis and poor outcomes after sepsis have been well documented in patients with diabetes and CKD.44,45 In the present study, we observed lower sepsis- and infection-related mortality in the GLP-1 receptor agonist group than in the DPP-4 inhibitor group. Incretin-based therapy might mitigate excessive inflammation and microvascular thrombosis in sepsis via activation of the GLP-1 receptor.46,47 However, differences in the infection-related outcomes (including outcomes of COVID-19) between patients receiving DPP-4 inhibitor and GLP-1 receptor agonist treatment have been observed.48,49 Increased mortality was seen in the population of patients with diabetes and COVID-19 treated with DPP-4 inhibitors (HR, 1.07; 95% CI, 1.01-1.13).48 In consideration of the burden of sepsis-related mortality in populations with advanced CKD and ESKD, the findings of the present study deserve further prospective trials for confirmation.

We observed that MACCE-related mortality did not differ between the 2 groups, which was similar to the result from a study of the general population with diabetes.7 Similar findings were observed in patients with ESKD in whom the cardiovascular protective effect of statins was lost.50-53 Previously published randomized clinical trials and real-world observational studies50-53 revealed that use of statins for patients with ESKD or stage 5 CKD who were not receiving dialysis did not provide cardiovascular benefit. Gupta et al54 reported that a statin prescription was associated with a lower risk of sepsis events. Furthermore, the relatively short follow-up period and small sample size in the present study might be the reason that we did not observe lower MACCE-related mortality among patients treated with GLP-1 receptor agonists. In summary, we observed lower all-cause mortality and sepsis-related mortality but not lower MACCE-related mortality in the GLP-1 receptor agonist group compared with the DPP-4 inhibitor group. The study could not assess causal relationships, and an explanation for our finding is unclear.

논의

이 연구의 주요 결과는 다음과 같이 요약될 수 있습니다:

(1) 당뇨병 및 5단계 만성 신장 질환(CKD) 또는 말기 신장 질환(ESRD) 환자에게 GLP-1 수용체 작용제를 투여한 경우 DPP-4 억제제 투여에 비해 전체 사망률이 낮았으며,

(2) GLP-1 수용체 작용제 투여는 DPP-4 억제제 투여에 비해 패혈증- 및 감염 관련 사망률이 낮았습니다.

이전 연구에서는 일반 당뇨병 환자에서 GLP-1 수용체 작용제 사용이 위약 대비 전체 사망률, 심혈관 관련 사망률, 신부전 발생률이 낮다는 결과가 보고되었습니다.7 해당 연구에서 GLP-1 수용체 작용제는 설포닐우레아, DPP-4 억제제, 티아졸리딘디온과 비교하여 임상 결과가 개선되었습니다. 그러나 대규모 무작위 임상 시험(Liraglutide Effect and Action in Diabetes: Eval‎uation of Cardiovascular Outcome Results [LEADER] 시험13 및 Researching Cardiovascular Events With a Weekly Incretin in Diabetes [REWIND] 시험14)에서 GLP-1 수용체 작용제의 임상 효과를 평가한 결과, 만성 신장 질환(CKD) 또는 말기 신장 질환(ESKD) 환자의 비율이 작았습니다. 당뇨병과 말기 CKD 또는 ESKD를 동반한 환자에서 GLP-1 수용체 작용제 치료의 실제 세계 증거는 부족합니다. 본 연구에서 당뇨병과 말기 CKD 또는 ESKD를 동반한 환자에서 GLP-1 수용체 작용제 그룹의 전체 사망률이 DPP-4 억제제 그룹보다 낮은 것은 Palmer 등7의 결과와 일치합니다.

DPP-4 억제제와 GLP-1 수용체 작용제 간의 차이는 이전에 연구되었습니다.7,24-43 두 약물은 인크레틴 경로를 기반으로 하지만, DPP-4 억제제와 GLP-1 수용체 작용제는 임상적 효과가 다릅니다.-4 억제제와 GLP-1 수용체 작용제 간의 차이는 이전에 연구되었습니다.7 ,24-43 두 약물은 인크레틴 경로를 기반으로 하지만, DPP-4 억제제와 GLP-1 수용체 작용제는 임상적 효능에서 차이를 보였습니다.25 -43 헤모글로빈 A1c 수치 감소,24 -34 체중 감소 증가,25 -27,31-33,35-40 베타 세포 기능 개선,25 ,26,28,33,36 심장 기능 개선,27 ,41,42 및 알부민 수치 감소27 ,42,43이 관찰되었습니다. 무작위 임상 시험에서 GLP-1 수용체 작용제와 DPP-4 억제제를 비교한 결과입니다. GLP-1 수용체 작용제와 DPP-4 억제제 사이의 임상적 혜택 차이(즉, 더 나은 혈당 조절, 대사적 혜택)는 GLP-1 수용체 작용제를 투여받은 환자가 DPP-4 억제제를 투여받은 환자보다 더 나은 결과를 보인 이유를 설명할 수 있습니다.7 이러한 차이는 보충 자료의 eTable 5에 요약되어 있습니다.

당뇨병과 만성 신장 질환(CKD)을 가진 환자에서 패혈증에 대한 취약성과 패혈증 후 불량한 결과가 잘 문서화되어 있습니다.44,45 본 연구에서 우리는 GLP-1 수용체 작용제 그룹에서 DPP-4 억제제 그룹보다 패혈증 및 감염 관련 사망률이 낮았음을 관찰했습니다. 인크레틴 기반 치료는 GLP-1 수용체 활성화 통해 패혈증 시 과도한 염증과 미세혈관 혈전증을 완화할 수 있습니다.46,47 그러나 DPP-4 억제제와 GLP-1 수용체 작용제 치료를 받은 환자 간 감염 관련 결과(COVID-19 결과 포함)에 차이가 관찰되었습니다.48,49 DPP-4 억제제를 투여받은 당뇨병 및 COVID-19 환자 집단에서 사망률이 증가했습니다(HR, 1.07; 95% CI, 1.01-1.13).48 만성 신장 질환(CKD) 및 말기 신장 질환(ESKD) 환자 집단에서 패혈증 관련 사망률의 부담을 고려할 때, 본 연구의 결과는 추가적인 전향적 연구를 통해 확인이 필요합니다.

MACCE 관련 사망률은 두 그룹 간 차이가 없었으며, 이는 당뇨병을 가진 일반 인구 대상 연구 결과와 유사했습니다.7 ESKD 환자에서 스타틴의 심혈관 보호 효과가 상실된 경우 유사한 결과가 관찰되었습니다.50-53 이전에 발표된 무작위 임상 시험 및 실제 세계 관찰 연구50-53은 투석 치료를 받지 않는 ESKD 또는 5단계 CKD 환자에서 스타틴 사용이 심혈관 혜택을 제공하지 않았음을 보여주었습니다. Gupta 등54은 스타틴 처방이 세균성 쇼크 사건 위험 감소와 연관되었다고 보고했습니다. 또한 본 연구의 상대적으로 짧은 추적 관찰 기간과 작은 표본 크기가 GLP-1 수용체 작용제 치료 환자에서 MACCE 관련 사망률이 낮지 않았다는 결과의 원인이 될 수 있습니다. 요약하면, 우리는 GLP-1 수용체 작용제 그룹에서 DPP-4 억제제 그룹에 비해 전체 사망률 및 세균성 패혈증- 관련 사망률이 낮았지만 MACCE 관련 사망률은 낮지 않았습니다. 본 연구는 인과 관계를 평가할 수 없었으며, 우리 결과의 설명은 명확하지 않습니다.

Limitations

This study has several limitations. First, this was a retrospective cohort study lacking detailed information on clinical factors (eg, glucose control) and other factors that might confound the outcome (eg, smoking, body weight control). Some important factors such as mean estimated glomerular filtration rate, mean blood pressure, lipid control level, and the degree of albuminuria in patients who did not have ESKD were also unavailable for analysis in the NHIRD data set. Second, we could not examine the dose effect, and the indication of drug prescription might have resulted in differences between the 2 study groups. The lack of a protocolized approach to DPP-4 inhibitor treatment initiation should be noted. Furthermore, the national health insurance system in Taiwan covers a GLP-1 receptor agonist prescription only when patients have known cardiovascular disease, cerebrovascular disease, or poor glucose control despite other treatment. This policy also may have resulted in potential heterogeneity between the GLP-1 receptor agonist and DPP-4 inhibitor groups. To overcome this problem, we used the propensity score weighting method with the Charlson Comorbidity Index and as many covariates as available. Third, drug adherence could not be eval‎uated owing to the retrospective nature of the cohort design. Fourth, potential differences in treatment effects across subgroups might have existed, but owing to the relatively small sample size, we were unable to assess the significance of these differences across subgroups. Fifth, owing to the limited number of participants, we pooled patients with stage 5 CKD who were not receiving dialysis with those who had ESKD and were receiving dialysis. Patients with ESKD and those with CKD who were not receiving dialysis are 2 different populations. Furthermore, some patients with stage 5 CKD without a prescription for an erythropoiesis-stimulating agent were not included in this study. To overcome this baseline heterogeneity, we conducted a subgroup analysis to examine whether there was a significantly different treatment effect between these 2 populations.

Conclusions

In this cross-sectional study, in patients with type 2 diabetes and stage 5 CKD or ESKD, use of GLP-1 receptor agonists was associated with better outcomes, including all-cause mortality and sepsis- and infection-related mortality, compared with use of DPP-4 inhibitors. Additional large-scale, prospective studies are needed to examine our results.

Article Information

Accepted for Publication: January 13, 2022.

Published: March 7, 2022. doi:10.1001/jamanetworkopen.2022.1169

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Chen JJ et al. JAMA Network Open.

Corresponding Author: Huang-Yu Yang, MD, PhD, Kidney Research Institute, Department of Nephrology, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, No. 5, Fusing St, Gueishan District, Taoyuan City 333, Taiwan (hyyang01@gmail.com).

Author Contributions: Dr H.-Y. Yang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: J.-J. Chen, Huang, Tian, C.-W Yang, H.-Y. Yang.

Acquisition, analysis, or interpretation of data: J.-J. Chen, Wu, Jenq, Lee, Tsai, Tu, Huang, C.-L. Yen, T.-H. Yen, Y.-C. Chen, H.-Y. Yang.

Drafting of the manuscript: J.-J. Chen, Tu, C.-W Yang.

Critical revision of the manuscript for important intellectual content: Wu, Jenq, Lee, Tsai, Huang, C.-L. Yen, T.-H. Yen, Y.-C. Chen, Tian, H.-Y. Yang.

Statistical analysis: Jenq, Tsai, Tu, Huang, Y.-C. Chen, H.-Y. Yang.

Obtained funding: H.-Y Yang.

Administrative, technical, or material support: Lee, Huang, C.-L. Yen, T.-H. Yen, Tian.

Supervision: Huang, H.-Y. Yang.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by grant 108-2314-B-182-016-MY3 from the Ministry of Science and Technology, grants CORPG3H0731 and CORPG3J0641 from Chang Gung Memorial Hospital, and grant CLRPG3D0048 from the Maintenance Project of the Center for Big Data Analytics and Statistics at Chang Gung Memorial Hospital.

Role of the Funder/Sponsor: The Maintenance Project of the Center for Big Data Analytics and Statistics at Chang Gung Memorial Hospital had a role in the design and conduct of the study and collection, management, analysis, and interpretation of the data. The funders had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Hui-Tzu Tu, MS, and Yu-Tung Huang, PhD, Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Linkou, Taiwan, provided statistical assistance. They were not compensated for their work.

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