Sodium-glucose Cotransporter-2 Inhibitors與Dipeptidyl Peptidase-4 Inhibitors對於第二型糖尿病病人新生心房顫動風險之影響

研究目的：糖尿病是最常見的慢性疾病之一，除了會增加心肌梗塞的機率，同時也是心律不整的獨立危險因子，其中以心房顫動最為常見，故當糖尿病患者產生心房顫動時，對心血管疾病預後的影響比一般族群來的差，更容易引起中風甚至增加猝死的風險。第四型二肽基肽酶抑制劑(Dipeptidyl peptidase-4 inhibitors；DPP-4 Inhibitors)與第二型鈉-葡萄糖共轉運受體抑制劑(Sodium-glucose cotransporter inhibitors；SGLT-2 Inhibitors)為近年來新發展的口服降血糖藥物，現今研究顯示第四型二肽基肽酶抑制劑對於心血管疾病似乎無保護效果，但是第二型鈉-葡萄糖共轉運受體抑制劑被證實能改善糖尿病患者的死亡率及減少心衰竭住院的風險，然而目前並沒有明確的文獻報告指出DPP-4 Inhibitors與SGLT-2 Inhibitors對於新生心房顫動的影響，因此本研究的目的在於評估SGLT-2 Inhibitors對於新生心房顫動的風險影響與療效，建立更適當的用藥選擇，改善病人罹病率與死亡率。研究方法及資料：本研究屬於回溯型世代研究(retrospective cohort study)，使用中山醫學大學附設醫院病歷資料分析糖尿病患者16,773人，共11,976名糖尿病患者符合研究收案條件進行分析。實驗對象分為兩組：使用SGLT-2 Inhibitors為實驗組；使用DPP-4 Inhibitors為對照組。研究終點為首次心房顫動的診斷，又稱為新生心房顫動(New-onset atrial fibrillation)或試驗時間終點至2021年12月31日。利用「卡方檢定」、「傾向配對分析」、「生存曲線分析」及「Cox多變量分析」分析檢定。研究結果：實驗組3,437人曾使用SGLT-2 Inhibitors，對照組8,539人曾使用DPP-4 Inhibitors，以 Intention to Treat 的方式進行分析，因此換藥時仍以原組別進行分析。新生心房顫動風險分析，配對前實驗組發生率3.54，95% confidential interval: 2.34-5.15；對照組發生7.33，95% confidential interval: 6.15-8.68(log-rank p= 0.0006)。在傾向配對分析後使用SGLT-2 Inhibitors組比起對照組新生心房顫動風險比(Hazard ratio) 0.860，95% confidential interval: 0.488-1.516。Cox多變項分析粗風險比值0.476，95% confidential interval: 0.310-0.730。依據CHA2DS2-VASc score危險因子調整後的風險比0.646，95% confidential interval: 0.419-0.996。結果顯示實驗組的風險都比較低，傾向配對分析不具統計學上的顯著意義，但是依據CHA2DS2-VASc score作為Cox多變項分析調整後的風險比值具有統計學上的顯著差異。結論與建議： 本研究顯示糖尿病族群使用SGLT-2 Inhibitors有減少新生心房顫動機率的趨勢，提供了糖尿病合併CHA2DS2-VASc score危險因子時，使用SGLT-2 Inhibiors可以降低新生心房顫動機率，也間接證實SGLT-2 Inhibiors用於心血管的益處，包括降低心衰竭住院及死亡率機轉的解釋。

Objective：Type II diabetes mellitus is one of the most common chronic diseases. In addition to increasing the probability of myocardial infarction, type II diabetes mellitus also is an independent risk factor for arrhythmia. Atrial fibrillation is the most common cardiac arrhythmia. So when patients with diabetes mellitus have comorbidity in atrial fibrillation, the impact on the prognosis of cardiovascular disease is worse than the general population, and high risk to cause stroke or sudden death. Sodium-glucose cotransporter inhibitors(SGLT-2 Inhibitors) are newly developed anti-diabetes medicine in recent years, had been shown to improve mortality and reduce the risk of hospitalization in patients with or without diabetes mellitus. There is no clear literature to support SGLT-2 Inhibitors could reduce the new-onset atrial fibrillation risk, the purpose of this study is to evaluate the new-onset atrial fibrillation risk between SGLT-2 Inhibitors and DPP-4 Inhibitors and prove appropriate medical options in type II diabetes mellitus. Methods and Materials：This study is a retrospective cohort study, We collected the medical records of the Chung Shan Medical University Hospital to analyze 16,773 patients with type II diabetic mellitus, a total of 11,976 patients were enrolled. The patients were divided into two groups: (1) SGLT-2 Inhibitors users who took SGLT-2 Inhibitors for the experimental group, and (2) DPP-4 Inhibitors users who took DPP-4 Inhibitors for the control group. The study endpoint was the new-onset atrial fibrillation date or the end of the study period (December 31, 2021). Results：A total of 3,437 SGLT-2 Inhibitors users and 8,539 DPP-4 Inhibitors users were analyzed in Intention to Treat. For the new-onset atrial fibrillation risk analysis, the incidence rate of the SGLT-2 Inhibitors group before propensity score matching was 3.54, 95% confidential interval: 2.34-5.15, and the incidence rate of the control group was 7.33, and the 95% confidential interval was 6.15-8.68(Log-rank p=0.0006). After propensity score matching hazard ratio 0.86(95% confidential interval: 0.488-1.516) for new-onset atrial fibrillation risk in the SGLT-2 Inhibitors group compared to control groups. Cox multivariate regression showed a crude hazard ratio 0.476(95% confidential interval: 0.310-0.730), and the adjusted hazard ratio was 0.646(95% confidential interval: 0.419-0.996). The risk of the experimental group was relatively low, and the propensity score matching analysis was not statistically significant, but the adjusted risk ratio of Cox multivariate analysis had a statistically significant difference from the adjusted CHA2DS2-VASc risk score.Conclusion and Suggestion：This study showed a tendency that SGLT-2 Inhibitors reduce the rate of the new-onset atrial fibrillation risk in patients with type II diabetes mellitus and proved that patients with type II diabetes mellitus combined with CHA2DS2-VASc score risk factor could reduce the new-onset atrial fibrillation risk that indirectly explains the mechanism of the cardiovascular benefits of SGLT-2 Inhibitors.