沒有照片 作者: 呂瑾立
班別: 碩士班
畢業年度: 100
指導老師: 李中一
論文題目: 第一型糖尿病之流行病學特徵以及嚴重低血糖併發症對罹患心血管疾病風險及全死因死亡率的影響

[ 摘要 ]
過去一、二十年,第一型糖尿病的發生率在大部分西方國家都呈現快速增加的趨勢。「衛生假說」是當前解釋第一型糖尿病發生率變化的重要假說之一。雖然大部分第一型糖尿病都在病人年紀很輕的時候被診斷出來,但是有關亞洲國家兒童的第一型糖尿病及其重要的併發症「嚴重低血糖事件」的發生率,卻鮮少有文獻報告過。嚴重低血糖是血糖控制過程中一個主要的絆腳石。嚴重低血糖的發生是否對於後續的全死因死亡率或心血管疾病的發生率有長期的負面影響?其影響是否呈現劑量效應關係?仍然沒有定論。
本研究有關歷年兒童第一型糖尿病發生率的報告,是從2003到2008年的台灣健保資料庫中擷取而得。我們從重大傷病檔中取得因第一型糖尿病而被登錄重大傷病名單的新診斷個案資料,輔以內政部人口統計資料,計算出兒童第一型糖尿病的發生率和臨床特性。並且透過生態研究設計,檢驗了第一型糖尿病與居住地區兒童人口密度和都市化程度的相關性。此外,我們針對2003年到2011年的第一型糖尿病盛行病例世代,透過平均6.2年的追蹤時期,我們在卜瓦松分布的前提下,估計了這些病患嚴重低血糖的發生率和發生頻率,並探討了其可能的危險因子。我們更進一步的探討嚴重低血糖的發生對於全死因死亡率和心血管疾病發生率的影響。我們在巢式病例對照研究的設計中,採用發生機率密度取樣的配對法,探討在死亡或發生心血管疾病的一年前、一到三年前或三到五年前有無經歷過嚴重低血糖事件,以及事件發生前五年內累計的嚴重低血糖發生次數,與全死因死亡率和心血管疾病發生率的相關性及劑量效應關係。我們另外並建立了兩個世代追蹤研究,一個採用固定時間區間的嚴重低血糖暴露資料;一個則將嚴重低血糖視為時間相依變項,採用不同時間重覆測量的嚴重低血糖暴露資料。在上述所有三種研究設計中,嚴重低血糖事件與全死因死亡率和心血管疾病發生率的相關性估計,都調整了初次診斷年齡、性別、社會經濟因素、以及糖尿病嚴重度指標的干擾效應。
本研究發現,2003到2008年間,台灣兒童第一型糖尿病發生率為每十萬人5.3人。較高的發生率與女性、年紀較長、以及居住在兒童人口密度較低的地區有關。糖尿病酮酸毒血症仍然是這類病人住院的主要診斷之一。嚴重低血糖的發生率為每100個人年發生2.80人次或6.03個事件。較高的嚴重低血糖發生率與女性、較長的年紀、以及較低的健保月投保薪資有關。另外,根據巢式病例對照研究的結果,全死因死亡率與死亡前1年內、1-3年內、3-5年內曾經發生嚴重低血糖事件顯著相關,但是心血管疾病發生率則只有跟發病前一年曾經發生嚴重低血糖事件顯著相關。發病或死亡前五年累計的嚴重低血糖發生次數越高,全死因死亡率及心血管疾病發生率越高。從另外兩個世代追蹤研究的結果看來,嚴重低血糖的發生與短期及長期內的全死因死亡率都顯著相關。不過,只有當我們把嚴重低血糖當作時間相依變數的研究下,嚴重低血糖依然與短期及長期內的全死因死亡率都顯著相關,而在只採用固定時間測量嚴重低血糖狀態的研究中,嚴重低血糖只與第3-4年追蹤期間的心血管疾病發生率顯著相關。
總結來說,台灣的兒童第一型糖尿病發生率與西方國家比起來相對較低。女性、初次診斷的年齡較大、以及收入較低,與較高的嚴重低血糖發生率有關。曾經發生嚴重低血糖與短期或長期內發生全死因死亡率的風險有關,與短期內發生心血管疾病的風險有關。嚴重低血糖事件累計發生次數越多,全死因死亡率和心血管疾病發生率越高。臨床醫療人員與第一型糖尿病病患在進行血糖控制時,應多費心預防嚴重低血糖事件的發生率。
 
[ 英文摘要 ]
The incidence rate of Type 1 diabetes (T1DM) increased rapidly in most Western countries during last decades. Hygiene hypothesis is one of the major hypotheses explaining the variation of incidence rate. Most T1DM is diagnosed at young age, but the population incidence of childhood T1DM and the major complication, severe hypoglycemia, were rarely reported in Asian. Severe hypoglycemia is the major obstacle in glycemic controls. Whether there is a long-term association and a dose-gradient relationship between severe hypoglycemia and subsequent risks of all-cause mortality and cardiovascular disease (CVD) incidence is still inconclusive.
We retrieved our data from Taiwan’s National Health Insurance Research Database (NHIRD) from 2003 to 2008 to report annual incidence rate of childhood T1DM. By counting the newly-diagnosed T1DM registered in the list of Catastrophic Illness Database in NHIRD and using the population statistics from Taiwan’s government, we reported the incidence rate and clinical features of childhood T1DM, and examined the association of the incidence rate of T1DM with child-population density and urbanization level of living areas in an ecological study. Besides, a T1DM cohort was followed from 2003 to 2011, with a mean follow-up period of 6.2 years, to estimate the incidence rate and frequency of severe hypoglycemia under the assumption of Poisson distribution. The possible risk factors for the incidence of severe hypoglycemia in T1DM cases were examined. Furthermore, by taking all-cause mortality and cardiovascular disease (CVD) incidence as separate outcomes, we employed incidence density sampling matching method to conduct two nested case-control studies, in which the exposure status of severe hypoglycemia in three time-windows (1-year, 1-3 years, and 3-5 years) prior to the two adverse outcomes were determined and associated with the risks of all-cause mortality and CVD incidence. The dose-gradient effect of severe hypoglycemia within 5 years was also investigated. In addition, we also conducted two cohort studies, one with a fixed-time exposure status of severe hypoglycemia, and the other one with time-dependent exposure status of severe hypoglycemia. The independent effect of severe hypoglycemia on all-cause mortality and CVD incidence were assessed in the three aforementioned three studies, with adjustment or matched for age at first diagnosis, sex, socioeconomic factors, and severity of diabetes.
The childhood incidence rate was 5.3 per 105 persons in Taiwan from 2003 to 2008. An increased incidence rate of T1DM was associated with female sex, older age, and lived in the areas with lowest child-population density. Diabetic ketoacidosis was still the most important cause for hospitalization. The incidence rate of severe hypoglycemia in T1DM was 2.80 persons per100 person-years (PYs) and 6.03 episodes per 100 PYs. An increased incidence rate of severe hypoglycemia was associated with female sex, older age, and lower monthly-income based insurance premium. Moreover, according to results of the nested case-control design, the risk of all-cause mortality was associated with history of severe hypoglycemia occurred in 1-year, 1-3 years, and 3-5 years prior to death, but the risk of CVD incidence was only associated with history of severe hypoglycemia occurred in the previous year. A higher frequency of severe hypoglycemia occurred within 5 years was associated with a higher risk of all-cause mortality and CVD incidence. The prior history of severe hypoglycemia was associated with both short-term and long-term risks of all-cause mortality in the two cohort studies. On the other hand, severe hypoglycemia was found to be associated with CVD incidence in the cohort study with time-dependent exposure status of severe hypoglycemia, but only significantly associated with the risk of CVD incidence in 3-4 year of follow-up in the cohort design with fixed-time exposure status of severe hypoglycemia.
In conclusion, the incidence rate of childhood T1DM in Taiwan was relatively low compared to most Western countries. Among patients with T1DM, female sex, older age of first diagnosis, and lower income level were associated with an increased risk of severe hypoglycemia. Prior history of severe hypoglycemia was associated with both short-term and long-term risk of all-cause mortality and short-term adverse effect on CVD incidence. Higher frequency of severe hypoglycemia attack was associated with elevated risks of all-cause mortality and CVD incidence. Clinicians and patients with T1DM should put emphasis on the prevention of severe hypoglycemia while managing glycemic control.
 
住址: 台南市大學路一號 1 University Road, Tainan, TAIWAN 701    TEL: 06-235- 3535 EXT 5561 or 5562    傳真: 06-2359033    email: em75561@email.ncku.edu.tw