口服降糖药可降低糖尿病患者类风湿关节炎的发病风险!磺脲类vs二甲双胍,二者谁更优?

2022-08-18 liangying MedSci原创

在降低RA发生方面,双胍类药物的起效似乎比磺脲类药物更快,但磺酰脲类药物降低RA发生率的作用可能更长

糖尿病(DM)与代谢免疫风险相关,并且容易导致微血管和大血管事件的发生、靶器官损伤以及感染风险的升高。胰岛素分泌和(或 )作用缺陷而引起机体代谢系统紊乱是主要的病理产生机制。近年来有研究显示 ,糖尿病与其他自身免疫性疾病存在相似的遗传学基础,也属于自身免疫疾病。已有研究发现消除免疫途径可减轻DM小鼠的胰岛素抵抗。

糖尿病发病免疫机制

在一些大型临床试验中,糖尿病的最佳治疗与总死亡率和共病率的改善相关。在糖尿病的所有口服药物中,磺脲类或双胍类药物是最常用且公认的成本效益高的药物。根据英国前瞻性糖尿病研究的结果,磺脲类药物或胰岛素和双胍类药物(如二甲双胍)的强化血糖控制显著改善了超重患者10年随访的健康结果。

类风湿关节炎(RA)的发病机制涉及遗传背景、肥胖、慢性感染和环境因素,如口腔卫生、吸烟和饮食等,这些因素可影响口腔和肠道微生物群,从而间接影响RA的发展。RA和DM之间的相似性非常深刻,都有多样性免疫标记物参与和心血管疾病的严重共病性。

类风湿关节炎发病免疫机制

有学者在研究中发现,RA患者发生心血管疾病的风险更高 ,推断可能与炎症状态引发血脂、血糖等代谢紊乱存在一定关联。但现阶段医学界并未就 RA对血脂血糖的影响达成一致认识 ,但RA患者并发糖尿病的风险较正常人群更高,且 RA患者在高炎症状态下发生胰岛素抵抗的几率与低炎症状态患者相比更低。有证据表明,用磺脲类或双胍类药物治疗糖尿病可提高自身免疫性疾病的死亡率,抗氧化剂药物有可能对糖尿病小鼠产生保护作用。

为了确定磺脲类药物或双胍类药物是否延迟RA的发展,有研究者使用全国性数据库进行了一项队列研究,以检查磺脲类或双胍类药物对DM患者RA发展的影响。

该数据库包含台湾所有保险索赔数据,包括门诊、急诊和住院。从总体受益人中抽取了100万名受试者,并从1997年至2013年收集了他们的数据。研究人群由糖尿病患者组成,通过医生的诊断和疾病代码(ICD-9 CM代码:250)结合降糖药物处方确定。排除有1型糖尿病或RA病史的患者。

此外,还记录了所有口服降血糖药物的首次处方日期,如磺脲类、二甲双胍、α-葡萄糖苷酶、噻唑烷二酮类、美格替尼、二肽基肽酶-4抑制剂(DPP-4抑制剂)和胰岛素。使用分类变量卡方检验、Cox比例风险回归和log-rank检验来探讨DM患者发生RA的时间。采用Logistic回归方法估计RA在不同剂量药物照射下的比值比。

糖尿病患者基线使用的降糖药情况(确诊糖尿病后1年内至少90天处方)

最后共纳入94141例糖尿病患者。在每次分析中,将DM组中非磺脲类/双胍类药物使用者患RA的风险作为参考,使用磺脲类或双胍的DM患者的RA校正危险比为0.73(95%置信区间为0.60–0.90)。在指数日期前1年内,与未使用双胍类药物的患者相比,使用双胍类药物超过180天的患者患RA的风险显著降低。同样,在首次RA就诊的指数日期前2年或3年内服用磺脲类药物超过365天的DM患者中,仍观察到RA风险显著降低(均p<0.05)。

2糖尿病患者发生类风湿性关节炎的风险

糖尿病患者口服降糖药累积类风湿性关节炎发病率比例的Kaplan-Meier曲线

在嵌套病例对照分析中,研究者比较了双胍类药物或磺脲类药物的处方天数。在指数日期前1年内,与未使用双胍类药物的患者相比,使用双胍类药物超过180天的患者RA风险显著降低(aOR 0.72;95%CI 0.53–0.99)。在第一次类风湿关节炎就诊的指标日期前2年或3年内,比较按双胍类药物处方天数分类的组,类风湿关节病风险没有显著差异。

相反,1年内磺脲类药物的处方天数与RA风险显著相关(aOR 0.61,95%CI 0.45–0.83),趋势的p值具有统计学意义(p=0.0008)。在首次RA就诊的指数日期前2年或3年内服用磺脲类药物超过365天的DM患者中,仍观察到RA风险显著降低。

巢式病例对照研究设计评价双胍类和磺脲类药物的处方天数

另一项研究的证据表明,在患有自身免疫性疾病的普通患者中,与未服用双胍药物的患者相比,双胍与全因死亡率和年入院率显著降低相关。目前的研究已经开始确定磺脲类药物或双胍类药物对降低RA疾病发生率的作用。一般来说,磺脲类或双胍类药物的使用可能会降低RA的累积概率。

此外,使用替代标记物时也考虑了DM和RA的几个重叠危险因素。例如,吸烟是RA和DM的风险因素,因此将慢性阻塞性肺病作为替代标志物纳入了分析的混杂因素中。西方饮食或高脂饮食是众所周知的糖尿病风险因素,也可能是RA风险因素,因此,将血脂异常和慢性肝病(如脂肪肝)作为替代标志物纳入分析的混杂因素中。

至于α-葡萄糖苷酶抑制剂、噻唑烷二酮类或DPP-4抑制剂,一些小队列研究可能显示抗炎作用的益处,但在降低RA风险方面没有发现统计学意义。另一项使用同一台湾国家健康保险数据库的研究显示女性DM患者的RA发病率较高,另一项研究发现了相反的结果。而目前的研究则提示药物也可能影响DM患者的RA发病率。

总之,目前的研究发现磺脲类药物或双胍类药物的使用与糖尿病患者RA发生率较低相关。在降低RA发生方面,双胍类药物的起效似乎比磺脲类药物更快,但磺酰脲类药物降低RA发生率的作用可能更长,这一发现值得今后进一步研究。

参考文献:

1.Su YJ, Huang JY, Chu CQ, Wei JC. Sulfonylureas or biguanides is associated with a lower risk of rheumatoid arthritis in patients with diabetes: A nationwide cohort study. Front Med (Lausanne). 2022 Jul 27;9:934184. doi: 10.3389/fmed.2022.934184. 

2.Lin CY, Wu CH, Hsu CY, Chen TH, Lin MS, Lin YS, et al. Reduced mortality associated with the use of metformin among patients with autoimmune diseases. Front Endocrinol. (2021) 12:641635. doi: 10.3389/fendo.2021.641635

3.谭源源. 糖尿病合并类风湿关节炎临床特点探讨[J]. 中国实用医药, 2016(1):41-43.

4.程渝, 韩佳丽, 陈聪,等. 类风湿关节炎及抗风湿药物对胰岛素抵抗及2型糖尿病的影响研究进展[J]. 中国医药, 2018, 013(001):150-153.

5. Lu MC, Yan ST, Yin WY, Koo M, Lai NS. Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study. PLoS ONE. (2014) 9:e101528. doi: 10.1371/journal.pone.0101528

6. Tentolouris A, Thanopoulou A, Tentolouris N, Eleftheriadou I, Voulgari C, Andrianakos A, et al. Low prevalence of rheumatoid arthritis among patients with pre-existing type 2 diabetes mellitus. Ann Transl Med. (2018) 6:399. doi: 10.21037/atm.2018.09.14

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    2022-08-19 lmm397
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