第二型糖尿病患者胰島素類似物和高血壓藥物使用與危及視力的糖尿病視網膜病變之相關性研究

Abstract

研究目的： 此研究之目的為評估年齡和性別對於台灣境內危及視力的糖尿病視網膜病變之盛行率和發生率的影響，並評估全身性藥物對於預防糖尿病視網膜病變惡化的效果，主要針對高血壓藥物及長效型胰島素類似物。 研究材料及方法； 研究材料乃由國家衛生研究院全民健康保險資料庫 2005年百萬抽樣歸人檔 (Longitudinal Health Insurance Database 2005)中所收集而得，於2005年間29165名第二型糖尿病患者之中，共有222例初次患有危及視力的糖尿病視網膜病變(STDR)。按照美國糖尿病視網膜病變早期治療研究(ETDRS)小組的分類，危及視力的糖尿病視網膜病變被定義為具有臨床意義的黃斑部水腫，或嚴重的非增生性糖尿病視網膜病變，或增生性糖尿病視網膜病變。以ICD-9-CM碼和處置碼來分析性別差異和年齡調整對於第二型糖尿病患者被確診患有危及視力的糖尿病視網膜病變(STDR)的之盛行率和發生率的影響。同時針對在2000至2011年間，20至100歲之第二型糖尿病患者之中，初次使用不同種類的高血壓藥物處方，追蹤STDR的發生率並使用Cox 比例風險模型來分析與高血壓藥物相關的風險。此外，也收集2004至2006年間，20至100歲之第二型糖尿病患者之中，初次使用長效型胰島素類似物(glargine and detemir)和中效型人類胰島素(NPH insulin)，追蹤STDR的發生率並使用Cox 比例風險模型來分析與長效型胰島素類似物相關的風險。 研究結果： 2005年至2011年間，隨著糖尿病人口數的增加，STDR的病例數也隨之增加。於2005年間STDR年齡調整的發生率及盛行率均沒有明顯的性別差異。兩性的STDR年齡調整盛行率在年齡40-59 及 60-79 這兩個族群明顯較高。針對有接受使用不同種類的高血壓藥物處方的STDR患者所做的粗估發病率顯示，利尿劑、alpha受體阻斷劑、β受體阻斷劑、血管收縮素轉換酶抑制劑(ACEI)、血管收縮素受體拮抗劑(ARB)和鈣通道阻斷劑(CCB)每年每千人分別為 16.45, 9.49, 12.81, 19.19, 17.63, 18.15。就獨立的基本特徵來看，ACEI與ARB使用者的風險明顯高於CCB使用者。若調整隨時間改變的合併用藥結果顯示，接受ACEI, ARB及CCB的患者的風險明顯高於使用β受體阻斷劑的患者，危險比率從1.18至1.55具統計學上顯著的意義。於32,395名符合條件的第二型糖尿病患者中，使用長效型胰島素類似物glargine與STDR改變的風險無關。然而，使用長效型胰島素類似物detemir卻與危及視力的糖尿病視網膜病變改變的風險有關。 結論： 性別在發病率上並沒有明顯的差異，我們的研究結果發現在台灣已確診為第二型糖尿病患者中，STDR發病案例有增加的趨勢，但整體STDR盛行率則有下降的趨勢。表示降低死亡率、改善糖尿病照護模式、早期發現可治療的糖尿病視網膜病變，皆對於盛行率的下降有正面的貢獻。我們的研究結果並不支持ACEI、ARB 及CCB 在11年追蹤期間對於降低糖尿病視網膜病變惡化的效果優於β受體阻斷劑。比較長效型胰島素類似物glargine和NPH胰島素,並無發現其對於危及視力的糖尿病視網膜病變的風險有明顯不同。然而，卻發現使用長效型胰島素類似物detemir的風險明顯高於NPH胰島素。對於使用長效胰島素類似物治療第二型糖尿病患者以防止其罹患危及視力的糖尿病視網膜病變的策略仍有待進一步的研究與後續追蹤，以便評估使用長效胰島素類似物來減緩糖尿病視網膜病變的惡化之適當的劑量與安全性。

Objectives: The aims of the study are to estimate age- and sex-specific prevalence and incidence of sight-threatening diabetic retinopathy in Taiwan and evaluate the effect of systemic drugs on prevention of diabetic retinopathy progression, focusing on antihypertensive drugs and long-acting insulin analogues. Materials and Methods: Data was collected from a representative database, Longitudinal Health Insurance Database (LHID) 2005, during 2005, on a total of 222 incident cases of patients with sight-threatening diabetic retinopathy (STDR) among 29,165 type 2 diabetic patients. Sight-threatening diabetic retinopathy was defined as clinically significant macular edema or severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy according to the classification of the Early Treatment Diabetic Retinopathy Study Research Group. Gender-specific and age-adjusted incidence and prevalence rates of STDR were analyzed for the patients with type 2 diabetes and STDR identified using ICD-9-CM codes and procedure codes. Type 2 diabetic patients aged 20-100 years, with at least one prescription for antihypertensive drugs between 2000 and 2011 were identified from Longitudinal Health Insurance Database (LHID) 2005. The incidence rates of STDR were followed and Cox proportional hazards models were used to analyze the risk associated with antihypertensive drugs. A retrospective cohort consisting of patients with type 2 diabetes aged ≥ 20 years and newly initiated on long-acting insulin analogues (glargine and detemir) and intermediate-acting human insulin were identified from the National Health Insurance database between January 2004 and December 2006 and categorized into different cohorts. Risk of developing STDR was determined by Cox proportional hazards models and compared between different cohorts. Results: The number of incident cases of STDR increased in line with the increasing diabetic population during 2005-2011. During 2005, no gender differences in the age-adjusted incidence and prevalence rates were observed. The prevalence of sight-threatening DR was significantly higher when patients were aged 40-59 and 60-79. The crude incidence rates of STDR among patients received thiazide diuretics, alpha-blockers, beta-blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB) were 16.45, 9.49, 12.81, 19.19, 17.63, and 18.15 per 1,000 person-years. Users of ACEI and ARB were associated with a significantly higher risk than CCB users, independent of baseline characteristics. After adjusting time-varying use of concomitant medications for propensity score (PS) matched or unmatched cohorts, the results showed that patients receiving ACEI, ARB and CCB were associated with a significantly greater risk compared with beta-blocker users. The hazard ratio varied from 1.18 to 1.55 with statistical significance. Of the 32,395 eligible patients, initiators of insulin glargine, insulin detemir and NPH insulin were identified for comparison through propensity score matching. Long-acting insulin analogue, glargine, was not associated with changed risk for STDR by intention-to-treat and time-varying use approaches between either matched or unmatched cohorts. However, patients treated with insulin detemir, were associated with significantly changed risk for sight-threatening DR while analyses were performed by different approach for matched and unmatched cohort. Conclusions: There was no significant difference in the incidence between genders. Our findings provide the evidence that the incident cases of STDR increased among identified type 2 diabetic patients, but the overall prevalence of STDR was in a declining trend in Taiwan, suggesting that decreased mortality rate, better diabetes management, and early detection of treatable DR might contribute to the prevalence patterns. Our study did not support a superiority of ACEI, ARB and CCB over beta-blockers for lowering the progression of DR over 11-year follow-up. While comparing long-acting insulin analogue, glargine, with NPH insulin, no significant difference in the risk of sight-threatening DR was found. However, significantly increased risk was detected in insulin detemir initiators compared with NPH insulin initiators. The strategies that aim at preventing DR by treating type 2 diabetic patients with long-acting insulin analogues remain further prospective studies with longer follow-up period to validate our observations within an appropriate dosage range and to further evaluate the safety of long-acting insulin analogues on reducing the progression of DR.