糖尿病患者服用降血脂藥物與罹患 視網膜病變風險之相關性

The Association between Lipid-Lowering Therapy and The Risk of Retinopathy in Patients with Diabetes

花逸茗(Yi-Ming Hua)

指導教授 ： 林双金

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2013年)

https://doi.org/10.6832/KMU.2013.00085

摘要

研究背景
視網膜病變為糖尿病晚期常見併發症之ㄧ。雷射手術常是視網膜病變的首選治療，卻往往受限於設備及技術人員，術後的副作用也是為人所詬病。因此，如何預防或是輔助性藥物治療成為相當迫切的需求。近年來相關研究指出，降血脂藥物可能有降低視網膜病變的風險或是延緩其惡化之效果，本研究目的即在於探討使用降血脂藥物與視網膜病變風險之相關性。

研究方法
本研究分成兩部分進行，第一部分為文獻回顧及整合性分析研究，我們利用 Review Manager 5.1將符合條件的文獻進行整合分析，探討使用降血脂藥物與視網膜病變惡化、新發生視網膜病變以及新發生白內障的風險之相關性。第二部分為台灣健保資料庫2005年百萬抽樣歸人檔之回溯性世代研究，收納1997-2008年間新診斷出糖尿病之患者，以累積劑量(cDDDs)來定義實驗組(使用大於或等於28 cDDDs)及對照組(使用小於28 cDDDs)，再進一步將實驗組分為使用statin組、單用statin組、fenofibrate組、單用fenofibrate組以及合併療法五組。利用COX regression分析其使用降血脂藥物與否與新發生視網膜病變之相關性並且調整可能影響因子。在次分組分析中，我們進一步分析不同降血脂藥物使用組合、不同特定族群、以及劑量依賴的相關性。

研究結果
在文獻回顧與整合分析研究中，共收錄了10篇文獻，其中包含4篇隨機臨床試驗及6篇觀察性研究。隨機臨床試驗整合分析結果發現使用降血脂藥物有延緩視網膜病變惡化的趨勢 (RR=0.72, 95% CI=0.51-1.01)，且移除掉品質較低的文獻後效果更加顯著(RR=0.63, 95%CI=0.63-0.75)，而觀察性研究之整合分析結果發現statin類藥品並不能顯著降低新發生白內障風險 (OR=0.94, 95%CI=0.87-1.01)。
在回溯性世代研究部分，經過排除及納入條件後共收錄了42,088位糖尿病患者，在調整可能影響因子後，與控制組相比，實驗組可降低罹患視網膜病變的風險 (HR=0.65, 95 CI%=0.62-0.69)。然而，直接比較不同藥物組合的結果發現合併療法比單用fenofibrate組有顯著的好處 (HR=0.65, 95 CI%=0.55-0.77)。針對特定族群的次分組分析中發現，在糖尿病病史大於五年以上的患者，降血脂藥物的效果即不顯著 (HR=0.96, 95 CI%= 0.88-1.04)。在劑量依賴分析中可看到越高累積劑量有越好的預防效果。

結論
文獻回顧及整合性分析結果顯示使用降血脂藥物有降低糖尿病視網膜病變惡化的趨勢，statin類藥品則無法減少白內障發生風險，而利用台灣資料庫分析結果發現，使用降血脂藥物可減緩視網膜病變風險，且statin類藥物與fenofibrate都有此效果，特別是在高累積劑量時更為顯著，但在糖尿病病史長達五年以上的族群此效果卻有限。

關鍵字

糖尿病 ； 降血脂藥品 ； 視網膜病變 ； 白內障 ； 整合性分析 ； 全民健康保險研究資料庫

並列摘要

BACKGROUND
Retinopathy is one of the most common complications of diabetes which brings economic burden all over the world. Laser treatment is an effective choice while combines with some limitation and side effect, so new adjuvant therapy or prevention is required. More studies showed that use of lipid-lowering agents could decrease the risk of retinopathy. Therefore, we conducted a meta-analysis and retrospective cohort study to evaluate the effect of lipid-lowering agents on the prevention of retinopathy.

METHODS
There were two parts in this study, one was meta-analysis and another was population-based retrospective cohort study. Literature search was conducted from the beginning of databases until March 2013. Studies were included if they were prescribed statins or fenofibrate, and evaluate the risk of retinopathy or cataract. Then Review Manager5.1was used to perform the meta-analysis.
In another part, we carried out a retrospective cohort study among patients with newly diagnosed diabetes from 1997.1.1 to 2008.12.31 by using Longitudinal Health Insurance Database (LHID 2005). Patients who used lipid-lowering agents before the diabetes diagnosis were excluded. Case and control were defined by cumulative DDD (cDDDs) of lipid-lowering agnets. Case group was those who used any lipid-drug more than 28 cDDDs. We also divided case group into five groups, including statins user group, fenofibrate user group, statin-alone group, fenofibrate-alone group and combination therapy of statin and fenfibrate to assess the effect of different lipid lowering agents. In addition, we conducted a subgroups analysis for some specific population to assess the effect. Besides, an analysis for dose-response was also conducted. Multivariable cox proportional hazards regression was used to estimate the association between lipid lowering agent and retinopathy.

RESULTS
A total of 10 articles (4 RCTs and 6 observational studies) that evaluated the effect of statins or fibrates for the risk of retinopathy or cataract were included. The observed risk ratio for the progression of retinopathy in these four RCTs was 0.72 (95% CI=0.51-1.01) based on a random effect model. We furthermore conducted a sensitivity analysis due to considerable heterogeneity (I2=68%) and then the overall risk ratio shifted from 0.72 to 0.63 and the heterogeneity decreased. The result of five observational studies showed that the use of statins had no effect on decreasing the risk of cataract compared with placebo (OR=0.94; 95%CI=0.88-1.02).
In another part, we identified 42,088 patients who were newly diagnosed as diabetes in 1997-2008. After adjustment, any lipid-drug user had lower risk of retinopathy compared with non-lipid drug users (HR=0.65, 95 CI%=0.62-0.69).The result of head-to-head comparison between combination therapy and fenofibrate-alone user showed that combination therapy was better (HR=0.65, 95 CI%=0.55-0.77). In addition, the result showed a dose-dependent toward the retinopathy. With more cDDDs, the risk of retinopathy decreased dramatically. However, in the subgroup analysis for specific population, the protective effect of lipid-lowering therapy decreased in the group of patients with longer diabetes duration.

CONCLUSIONS
The meta-analysis indicated an association between lipid-lowering agents and the risk of retinopathy progression; however, statins didn’t seem to have benefit on the prevention of cataract. Patients newly diagnosed as diabetes would decrease the risk of retinopathy by lipid-lowering therapy. Both statin and fenofibrate had the benefit especially with higher cDDDs. But there was a limited effect for patients whose diabetes duration was longer than five years.

並列關鍵字

Diabetes ； statins ； fenofibrate ； retinopathy ； meta-analysis ； National Health Insurance Database

參考文獻

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