Nationwide Cohort Study for Efficacy and Safety of Statin-based Therapy : Part I. Efficacy of statin-antihypertensive combination therapy for primary prevention of major adverse cardiovascular and cerebrovascular events. Part II. Impact of statin therapy on the incidence of diabetes mellitus in patients with coronary heart disease.
- 주제(키워드) statin , antihypertensive , major adverse cardiovascular and cerebrovascular events , cohort study , NHIS , HIRA , claims database , diabetes mellitus , coronary heart disease
- 발행기관 아주대학교
- 지도교수 Sukhyang Lee
- 발행년도 2020
- 학위수여년월 2020. 8
- 학위명 박사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000030088
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
PART I: Efficacy of statin-antihypertensive combination therapy for primary prevention of major adverse cardiovascular and cerebrovascular events BACKGROUND: Atherosclerotic cardiovascular (CV) diseases and their risk factors (dyslipidemia, hypertension, and type II diabetes mellitus) are the leading causes of morbidity and mortality worldwide. Management of these conditions are critical, however, the treatment rates are low. Moreover, dyslipidemia and hypertension are considered independent CV risk factors and population with both conditions are increasing. Combination therapy attempting to manage both cholesterol and blood pressure (BP) would minimize cardiovascular and cerebrovascular events. A number of studies evaluating the efficacy of lipid- and BP-lowering combination therapies are ongoing, however, most use surrogate markers (i.e. changes in low-density lipoprotein cholesterol (LDL-c) or BP levels) as outcome measures. Therefore, the degree of combination therapy effects needs to be evaluated in real-world setting. OBJECTIVES: To evaluate whether statin plus antihypertensive agent(s) (statin plus angiotensin II receptor blocker (ARB), statin plus calcium channel blocker (CCB), and statin plus ARB and CCB) are more effective in reducing risk of major adverse cardiovascular and cerebrovascular events (MACCE) than statin therapy. METHODS: This is a population-based retrospective cohort study using National Health Insurance Service-National Sample Cohort database. The data corresponded to 1,113,656 individuals selected by stratified random sampling from January 1, 2002 to December 31, 2013. Patients were included if they 1) had at least one CV risk factor, 2) took statin therapy with or without antihypertensive agent(s) (ARB and/or CCB). Patients were excluded if they had a previous CV event. The primary outcome was MACCE, the composite of CV mortality, myocardial infarction, ischemic stroke, or revascularization. Propensity-score (PS) matching was performed between statin vs. statin plus ARB, statin vs. statin plus CCB, and statin vs. statin plus ARB and CCB at a 1:1 ratio. Incidence rates and hazard ratios (HRs) with 95% confidence intervals (CI) were estimated to appraise the differences between two cohorts. RESULTS: A total of 73,850 patients were identified before matching. After the matching, 9,251 patients each in statin and statin plus ARB cohorts, 13,189 in statin and statin plus CCB cohorts, and 3,207 in statin and statin plus ARB and CCB cohorts were included in the after-matching analysis. Compared to the statins, combination therapies were associated with lower rates of MACCE (statin plus ARB: 6.52% vs. 4.26%, HR 0.70 (95% CI 0.61 – 0.79), statin plus CCB: 7.61% vs. 6.51%, HR 0.86 (95% CI 0.79 – 0.95), statin plus ARB and CCB: 6.86% vs. 4.15%, HR 0.64 (95% CI 0.52 – 0.80)). Among the statin agents, atorvastatin was consistently associated with reduced rates of MACCE when used in combination with antihypertensive agents. CONCLUSION: Statin-antihypertensive combination therapy was more effective in reducing MACCE when compared with statin therapy. The magnitude of association was the most significant in statin plus ARB and CCB, the ‘triple’ combination therapy cohort. When indicated and the patient has compelling indications, it seems logical to consider the use of triple therapy to well-manage both conditions and thereby prevent further CV events. PART II: Impact of statin therapy on the incidence of diabetes mellitus in patients with coronary heart disease BACKGROUND: Although a new class of lipid-lowering agents has been introduced in the treatment of dyslipidemia, statins remain as the drug of choice for preventing atherosclerotic cardiovascular disease in patients with or without coronary heart disease (CHD). However, studies have raised concerns regarding the risk associated with statin use: the development of type II diabetes mellitus (T2DM). OBJECTIVES: To evaluate the association between statins and new-onset diabetes mellitus (NODM) in CHD patients with no history of diabetes. METHODS: This is a population-based retrospective cohort study using the Korea Health Insurance Review and Assessment Service (HIRA) claims database. Patients were included if they 1) were 18 years and older, 2) were diagnosed with CHD between January 1, 2009 and December, 31, 2012, 3) (in statin cohort) initiated statin during the index period (January to June 2010), 4) (in non-statin cohort) had no record of statin use at all, 5) were never diagnosed with T2DM. The primary outcome was NODM. Among adult patients with CHD, statin users and matched non-statin users were identified on a 1:1 ratio using proportionate stratified random sampling by sex and age. They were subsequently matched further using propensity-score with age and comorbidities to reduce the selection bias. Incidence rates, cumulative incidence rates and hazard ratios (HRs) with 95% confidence intervals (CI) between statin use and occurrence of NODM were estimated. RESULTS: A total of 156,360 patients (94,370 in the statin users and 61,990 in the non-statin users) were included in the analysis. The incidence rates of NODM were 7.8% and 4.8% in the statin users and non-statin users, respectively. The risk of NODM was higher among statin users (adjusted HR 1.84 (95% CI 1.63 – 2.09)). Pravastatin had the lowest risk (adjusted HR 1.54 (95% CI 1.32 – 1.81)) while those who were exposed to more than one statin were at the highest risk of NODM (adjusted HR 2.17 (95% CI 1.93 – 2.37)). CONCLUSION: Based on the current evidence, it appeared that all statin agents were associated with an increased risk of NODM in patients with CHD. Our finding was consistent with results from previous studies and we believe that our study would contribute to a better understanding of statin and NODM association by analyzing statin use in the real-world setting. Periodic screening and monitoring for diabetes are warranted during prolonged statin therapy in patients with CHD.
more초록/요약
PART I: 주요 심장 및 뇌혈관 사건의 일차 예방에 대한 스타틴-항고혈압제 병용요법의 효과 배경: 동맥경화성 심혈관 질환과 이의 위험요인 (이상지질혈증, 고혈압, 제2형당뇨)은 전세계적으로 질병 이환율과 사망률을 높이는 주요 원인이다. 이러한 위험 요인을 관리하는 것이 중요하다는 사실은 잘 알려져 있으나, 실질적인 치료율은 낮은 편이다. 더군다나, 이상지질혈증과 고혈압은 각각 독립적인 심혈관질환 위험요인이며 이 두 위험요인을 모두 가진 인구는 계속해서 늘고있는 추세이다. 콜레스테롤과 혈압을 동시에 낮출 추 있는 병용요법은 심장 및 뇌혈관 사건 발생을 낮추는 데 기여할 것이다. 현재, 복합제에 대한 연구가 끊임없이 진행중이지만, 이러한 연구의 대부분은 콜레스테롤이나 혈압과 같은 중간지표를 평가하는 게 대부분이다. 실제 임상에서 병용 요법의 효과가 얼마나 있을 지는 미지수이다. 목적: 스타틴-항고혈압제 병용요법 (스타틴-안지오텐신 Ⅱ 수용체차단제, 스타틴-칼슘통로차단제, 스타틴-안지오텐신 Ⅱ 수용체차단제-칼슘통로차단제)이 스타틴 단독요법과 비교해 주요 심장 및 뇌혈관 사건 (major adverse cardiovascular and cerebrovascular events (MACCE))을 낮추는 데 있어 더 효과적인지를 평가한다. 방법: 2002년 1월 1일부터 2013년 12월 31일까지 무작위 추출을 통해 선정된 1,113,656명이 포함된 국민건강보험 공단 표본 자료를 이용한 모집단-기반 후향적 코호트 연구이다. 심혈관 위험요인이 있으며, 스타틴+/-항고혈압제 (안지오텐신 Ⅱ 수용체차단제 +/-칼슘통로차단제) 복용을 시작한 환자가 연구대상이며 이미 심혈관 질환을 겪은 환자는 대상에서 제외하였다. 1차 평가변수는 MACCE (심혈관으로 인한 사망, 심근경색, 허혈성 뇌졸증, 또는 관상동맥재개술의 합)이다. 스타틴 단독요법을 기준으로 각각의 병용요법 코호트가 1:1의 비율로 성향점수 매칭 (propensity-score matching)이 되었다. 발생률 (incidence rate), 위험비 (hazard ratio, HR)와 95% 신뢰구간 (confidence interval, CI)을 산출하여 코호트간의 차이를 평가하였다. 결과: 매칭 전 총 73,850명의 대상 환자가 선정 되었고, 1:1 매칭 후 최종적으로 스타틴-안지오텐신 Ⅱ 수용체차단제 코호트 비교에 각각 9,251명씩, 스타틴-칼슘통로차단제 코호트 비교에 각각 13,189명씩, 스타틴-안지오텐신 Ⅱ 수용체차단제-칼슘통로차단제 코호트 비교에 각각 3,207명씩 포함되었다. 스타틴 단독요법과 비교해, 스타틴-항고혈압제 병용요법 복용환자군에서 MACCE 발생률 및 HR이 더 낮게 나타났다 (스타틴 vs. 스타틴-안지오텐신 Ⅱ 수용체차단제 코호트: 6.52% vs. 4.26%, HR 0.70 (0.61-0.79), 스타틴 vs. 스타틴-칼슘통로차단제 코호트: 7.61% vs. 6.51%, HR 0.86 (0.79-0.95), 스타틴 vs. 스타틴-안지오텐신 Ⅱ 수용체차단제-칼슘통로차단제 코호트: 6.86% vs. 4.15%, HR 0.64 (0.52-0.80)). 스타틴 제제 중에서는 atorvastatin이 항고혈압제과 병용으로 쓰였을 때 특정 subgroup과 관계없이 지속적으로 낮은 MACCE 발생률을 나타냈다. 결론: 스타틴 단독요법에 비해 스타틴-항고혈압제 병용요법이 MACCE를 낮추는 데 더 효과적이었으며, 그 효과가 스타틴-안지오텐신 Ⅱ 수용체차단제-칼슘통로차단제 코호트에서 가장 두드러지게 나타났다. 콜레스테롤과 혈압, 둘다 조절이 필요한 경우, 스타틴-안지오텐신 Ⅱ 수용체차단제-칼슘통로차단제 3제 요법을 고려하는 것이 심혈관 사건 일차 예방을 위해 중요하다. PART II: 관상동맥 심질환 환자에서의 스타틴 관련 신규 당뇨병 발생 연구 배경: 이상지질혈증 치료에 있어 새로운 계열의 약물이 등장하기도 했지만, 가이드라인은 여전히 스타틴을 콜레스테롤 치료 및 동맥경화성 심혈관 질환 예방의 1차 선택 약제로 사용을 권고하고 있다. 그러나, 몇몇 연구에서 스타틴 복용이 당뇨를 유발할 수 있다는 결과가 나오고 있다. 목적: 당뇨 병력이 없는 관상동맥 심질환 (coronary heart disease, CHD) 환자에서 스타틴 사용이 당뇨병 발병에 영향을 미치는 지 평가한다. 방법: 국민건강 심사평가원 청구자료를 이용한 모집단-기반 후향적 코호트 연구이다. 18세 이상이며, 당뇨 병력이 없고, 2009년 1월 1일1부터 2012년 12월 31일사이 CHD을 진단받은 환자가 대상이며, 스타틴 코호트는 2010년 1월 – 6월사이 스타틴을 복용 시작하고 non-스타틴 코호트는 연구기간 내 스타틴을 전혀 사용하지 않은 환자가 대상이다. 1차 평가 변수는 신규 당뇨병 발생 (new-onset diabetes mellitus, NODM)이다. CHD환자 중 스타틴 복용환자와 그렇지 않은 환자를 성별과 나이로 계층화추출법 (stratified random sampling)을 이용해 매칭시켰으며, 이후 다시 한번 propensity score 매칭을 하여 군간의 기저특성 차이를 최소화하였다. 발생률, 누적 발생률, HR을 산출하여 코호트간의 차이를 평가하였다. 결과: 총 156,360명 (스타틴 코호트: 94,370명, non-스타틴 코호트: 61,990명)이 최종분석에 포함되었다. NODM 발생률은 스타틴 코호트, non-스타틴 코호트에 각각 7.8%, 4.8%였으며 NODM 발생 위험도 스타틴 복용환자들에서 더 높게 나타났다 (adjusted HR 1.84 (1.63–2.09)). 스타틴 제제 중에서 pravastatin을 복용한 환자에서 NODM 위험이 가장 낮게 나타났으며 (adjusted HR 1.54 (1.32–1.81)), 여러 종류의 스타틴을 복용한 환자 (complex use)에서 NODM의 위험이 가장 높았다 (adjusted HR 2.17 (1.93–2.37)). 결론: 본 연구 결과에 따르면 모든 종류의 스타틴이 CHD 환자에 사용되었을 때 NODM 발생 위험을 높이는 것으로 보여진다. 이 결과는 이전 연구들의 결과와 일관되고, 스타틴 종류별 NODM 발생 위험도를 알아봄으로써 스타틴 관련 당뇨병 발병 이상반응에 대한 좀 더 자세한 이해를 돕는 데 기여했다고 할 수 있다. CHD 환자에게 스타틴을 사용할 때는 당뇨병 예방에 대한 주기적인 스크리닝과 모니터링이 중요할 것이다.
more목차
Part I. Efficacy of statin-antihypertensive combination therapy for primary prevention of major adverse cardiovascular and cerebrovascular events 1
Chapter I: Introduction 2
I-1. Prevalence and significance of cardiovascular diseases 2
I-2. Risk factors of ASCVD 3
I-2-1. Dyslipidemia and lipid-modifying agents 3
I-2-2. Hypertension and antihypertensive agents 7
I-3. Rationale and significance of the study 9
I-4. Objectives 11
Chapter II. Methods 12
II-1. Data source 12
II-2. Study Design 14
II-2-1. Patient selection 14
II-2-2. Demographics 17
II-2-3. Statins: individual agents and intensities 19
II-2-4. Assessment of medication exposure 21
II-2-5. Definitions of CV risk factors 21
II-2-6. Definitions of outcomes 21
II-3. Statistical analysis 24
II-4. Ethics approval 25
Chapter III. Results 26
III-1. Prevalence of patients with CV risk factors 26
III-2. Prevalence of medication use among patients with CV risk factors 28
III-3. Baseline characteristics 30
III-3-1. Demographics before PS-matching 30
III-3-2. Characteristics of statin therapy before PS-matching 34
III-3-3. Demographics of PS-matched population 36
III-3-4. Characteristics of statin therapy of PS-matched population 40
III-4. Outcome results in matched population 42
III-4-1. Comparison of efficacy outcomes: statin vs. Statin plus ARB 42
III-4-2. Comparison of efficacy outcomes: statin vs. Statin plus CCB 45
III-4.3. Comparison of efficacy outcomes: statin vs. Statin plus ARB and CCB 50
III-4-4. Comparison of efficacy outcomes by subgroups in matched population: statin vs. Statin plus ARB 55
III-4-5. Comparison of efficacy outcomes by subgroups in matched population: statin vs. Statin plus CCB 57
III-4-6. Comparison of efficacy outcomes by subgroups in matched population: statin vs. Statin plus ARB and CCB 59
III-4-7. Comparison of safety outcomes 61
Chapter IV. Discussion 63
IV-1. Summary of findings 63
IV-2 Interpretation of subgroup analysis 64
IV-3. Prescribing patterns of antihypertensive agents in Korea and rationale for selection of statin-antihypertensive(s) combination therapy 65
IV-4. Changes in prescribing patterns of statins in Korea 67
IV-5. Clinical implication of simultaneous cholesterol- and BP-lowering effects 68
IV-6. Availability of single-pill combination therapy and future directions 71
IV-7. Safety outcomes of statin-based therapies 73
IV-8. Strengths and limitations 75
Chapter V. Conclusion 77
Part II. Impact of statin therapy on the incidence of diabetes mellitus in patients with coronary heart disease 78
Chapter I: introduction 79
I-1. Four statin benefit groups defined by guidelines 79
I-2. A literature review of statin associated incident diabetes 80
I-3. T2DM as an independent risk factor of ASCVD 82
I-4. Underrepresentation of Asian ethnicity in clinical trials 83
I-5. Objectives 84
Chapter II. Methods 85
II-1. Data source 85
II-2. Study Design 86
II-2-1. HMG Co-A reductase inhibitors 86
II-2-2. Patient selection 86
II-2-3. Assessment of exposure and outcome definition 89
II-2-4. Definition and identification of NODM 91
II-2-5. Covariates 91
II-3. Statistical analysis 92
II-4. Ethics approval 93
Chapter III. Results 94
III-1. Study population 94
III-2. Demographics 95
III-3. Incidence rates and cumulative incidence of NODM 97
III-4. Hazard ratios of NODM 100
III-5. Subgroup analysis 102
Chapter IV. Discussion 105
IV-1. Results of the present study related to previous studies 105
IV-2. Age-related differences in statin therapy 107
IV-3. Interpretation of subgroup analysis 108
IV-4. Differences in diabetogenic effects of statins among different agents 109
IV-5. Diabetogenic effects of statins among different ethnic groups 110
IV-6. Possible explanation of diabetogenic effects of statins 112
IV-7. Strengths and limitations 115
Chapter V. Conclusion 117
References 118
Abstracts (in korean) 136
