| 摘要: | 背景
老年性黃斑部病變(Age-related macular degeneration, AMD)為黃斑部的退化性疾病，此疾病可能會導致失明，而近期有研究指出AMD可能與心血管的危險因子有關聯性。近年來有文獻指出statin類藥物可能和AMD的發生與進展有相關；而也有動物及體外實驗指出fibrate類藥品對於AMD可能具有潛在的保護性。然而目前對於statin類、fibrate類藥物的使用與AMD的發生之關連性研究較少，因此本研究致力於探討在三段不同觀察區間內，其statin類、fibrate類藥物的使用與AMD的發生之關連性。
研究方法
本研究使用分析資料取樣自國家衛生研究院所提供之全民健康保險資料庫承保抽樣歸人檔2000年版本(Longitudinal health insurance database, LHID 2000)，此研究為一回顧性世代研究。本研究觀察三段不同區間，包含：(1) A組：2001/01/01至2003/12/31。 (2) B組：2001/01/01至2005/12/31。 (3) C組：2001/01/01至2008/12/31。本研究病患收錄條件為大於18歲以上之成人，且必須確認兩次以上高血脂之診斷；而病患若其AMD診斷早於高血脂診斷則被排除。
而A、B、C組內又分成三組，實驗組為使用statin或fibrate類藥物之高血脂病患，且為了確保此用藥族群為慢性且規律服藥者，若高血脂之診斷日期起一年內其statin或fibrate類藥物使用天數小於90日之病患則將其排除。對照組(I)為有高血脂之診斷但並未使用statin或fibrate類藥物之病患；對照組(II)則利用年齡、性別、高血脂診斷年份與對照組(I)做1:1之配對。A、B、C組分別追蹤8年、6年、3年，若在追蹤期間內病患罹患AMD則停止追蹤。
在A、B、C組這三組中，其實驗組及對照組(I)人數分別為18,473人及9,747人(Ａ組)；29,600人及17,035人(B組)；44,874人及28,880人(C組)。本研究以Cox比例風險迴歸(Cox proportional hazard regression)來估計statin類、fibrate類藥物的使用與AMD的發生之關連性，並校正可能干擾因子。
研究結果
在A、B、C組這三組中，若與對照組(I)相比，若曾使用過statin類藥物之病患其發生AMD之風險皆會增加(p<0.001)；而曾使用過fibrate類藥物之病患則會降低發生AMD之風險(p<0.01)。然而，在A組中則觀察到若病患同時併用statin及fibrate類藥物或曾經使用過這兩種藥物，則會增加發生AMD之風險(p<0.01)。在劑量效應方面，在A、B、C組這三組中，在所有不同的追蹤時間內，若病患其statin使用大於360 DDD (defined daily dose, 定義每日劑量)則會增加發生AMD之風險；而fibrate類藥物使用 (大於 540 DDD)，皆會降低發生AMD之風險。
結論
在A、B、C三組中，statin類藥物的使用無論追蹤時間的長短及劑量的多寡，皆可能顯著增加AMD發生之風險，；而fibrate類藥物的使用只有在追蹤3年及6年這兩組且必須在高劑量時才可能降低AMD發生之風險。這項研究成果提供了未來對於statin類及fibrate類藥物在AMD治療角色上的應用，也同時提供了未來對於AMD藥物探索之一項基石。
Background
Age-related macular degeneration (AMD) is a progressive degenerative disease of the macular that may lead to blindness, and has been reported to be associated with several cardiovascular risk factors. Several studies have reported that statins are associated with the development and progression of AMD, while others have reported protective effect against the same. Also, recent in-vitro and animal experimental studies have also suggested that fibrates may have potential protective effects against AMD. However data are sparse on the association between statin and fibrate use and the risk of AMD over different follow-up periods. The aim of the present study, therefore, was to determine the association between statin and fibrate use and the risk of developing AMD across three different follow-up periods.
Methods
This was a retrospective cohort study using data from the Longitudinal Health Insurance Database 2000 (LHID 2000), a dataset of Taiwan’s National Health Insurance Research Database (NHIRD). Patients included in the study were those diagnosed with at least 2 episodes of hyperlipidemia after their 18th birthday in three different periods; between 1st January, 2001 and 31st December, 2003 (cohort A); between 1st January, 2001 and 31st December, 2005 (cohort B); between 1st January, 2001 and 31st December, 2008 (cohort C). Patients were excluded from this study if they had a history of AMD before diagnosis of hyperlipidemia.
Each of the three groups of hyperlipidemic patients was separated into two groups: those who received statin or fibrate (study group) and those who never received statins or fibrate (comparison group I). Patients in comparison group I in each of the three groups were matched by age, gender, and index year on a 1:1 ratio with a group of patients with no diagnosis of hyperlipidemia and never used any statin and/or fibrate (comparison group II). To ascertain inclusion of only chronic and regular users of statin or fibrate, we excluded patients who filled received statin or fibrate below 90 days within first year after the index date. Patients in all the three groups were followed up for 8 years (cohort A), 6 years (cohort B), and 3 years (cohort C) until patients get AMD diagnosis or reached the end of the study period as determined by the length of the follow-up period in each cohort.
Among the three follow-up cohorts, the respective total number of exposed hyperlipidemic patients (Study Group) and non-exposed Hyperlipidemic patients (Comparison Group I) were; 18,473 and 9,747 for cohort A; 29,600 and 17,035 for cohort B; 44,874 and 28,880 for cohort C. The index date of follow up period for patients who received statin or fibrate was defined as the first prescription date of statin or fibrate, whereas the index date of follow up period for patients who never received statin was defined as the date of hyperlipidemia diagnosis. The association between statin and/or fibrate use and the risk of AMD was compared across the three follow-up periods using hazard ratios, which were calculated using cox regression and adjusted for possible confounders.
Results
Compared with hyperlipidemic patients without drugs (comparison I), patients who received only statins showed a statistically significant increased risk of developing AMD (p˂0.001), while those who received only fibrates had a statistically significant protective effect (p˂0.01) at all three follow-up periods. However, receiving both statin and fibrate, was significantly associated (p˂0.01) with increased risk of AMD at 8 year follow-up period only. In dose-response analysis, patients who received over 180 DDDs (defined daily dose) of statin were associated with increased risk of AMD across all follow-up periods. For fibrates, high doses (> 540 DDD) were required at 3 year and 6 year follow-up durations to produce significant risk reduction. In the 8 year follow-up period, fibrate use was associated with significant risk reduction at a dose of at least 180 DDD. |
