痛风患者的福音！老降糖药从历史数据中脱颖而出
来源：倍可亲(backchina.com)
痛风者福音：钠-葡萄糖协同转运蛋白 2 抑制剂从历史数据中脱颖而出
倍可亲特稿，By Science 专栏作家 Lily / 有一次，我请一些朋友来家吃饭。 我精心准备了煮蟹腿、烤羊排、凉拌芦笋、蘑菇炖豆腐、和红豆沙。 我把冰箱塞满了各种各样的啤酒，当然，也为那些格外自律的人准备了一些瓶装水。我以为我的朋友们看到这些食物都会高兴坏了，哪知道，一位五十岁左右、身材略显丰腴的男士却苦笑着摇了摇头：“除了水以外，你准备的东西我都不敢碰。” 我立即意识到，这位朋友最近一定是痛风发作了，而我准备的所有食物，包括啤酒，都含有丰富的嘌呤，很容易使他的血尿酸水平升高，从而可能引发下一次痛风发作。天哪，我可没打算故意放毒害他！
在人类的数千种疾病中，痛风是少数几个拥有超悠久的历史的一个，它早在公元前2640年的古埃及就有记载。痛风还有一个响亮的名字：国王病。 之所以得此名，可能是因为过去只有国王才有特权享用丰盛的美食和不尽的美酒乃至得痛风。痛风曾幸运地伴随了诸多名人的痛苦一生，这些名人包括蒙古大汗忽必烈、亨利八世、贝多芬、克里斯托弗·哥伦布、本杰明·富兰克林等。 其实，如果不合并糖尿病、高血压、心肌梗塞或肾衰竭等其他疾病的话，痛风通常不致命。但痛风的症状，如许多人描述的，简直痛彻心扉，让人难以忍受，让人生无可恋。它的痛有如钢针穿骨，又有如巨轮碾压，让患者寝食难安，无心工作学习，甚至无法直立或行走。疼痛通常从大脚趾外关节开始，然后多个关节都变得又红又肿又痛，症状可能会持续几天到几周不等。最糟糕的是，当一切恢复正常，被犯关节完好如初，患者满以为可以享受些许安宁平静了，下一次发作可能毫无预警地汹涌而至，再次留下一片狼藉。
最近有些让痛风患者颇感安慰的好消息。众所周知，许多痛风患者都同时患有糖尿病，你看看大汗忽必烈和亨利八世的肖像，想必你也能猜出几成。钠-葡萄糖协同转运蛋白2抑制剂（SGLT2is）是一种自2014年以来一直被用于治疗II型糖尿病的药物。一些研究人员观察到，SGLT2is对糖尿病患者的心血管和肾脏系统有保护作用，且能降低患者的血尿酸水平。研究人员自然而然地意识到，SGLT2is 可能能够预防或缓解痛风。这个设想需要用小白鼠做动物实验来检验吗？ 谢天谢地，不用。分析海量的历史临床数据就够了。麻省总医院的风湿过敏和免疫学系的 Hyon K. Choi 和 Yuqing Zhu 团队，采用倾向性评分匹配和新用户队列匹配方法，分析了 2014 年 1 月 1 日至 2022 年 6 月 30 日期间痛风和 2 型糖尿病患者的通用人口数据库。这些患者在患病期间都接受过 SGLT2is 或二肽基肽酶 4 抑制剂 (DPP-4is) 治疗。和SGLT2is相似，DPP-4is 也是一种降糖药，但对降低血尿酸水平没有作用，所以正好适合当作对照。 研究人员根据急诊记录 (ED)、住院记录、门诊和配药等记录观察到，接受 SGLT2is 治疗的患者痛风复发率显着降低，心肌梗塞和中风的发生率也明显低于使用DPP-4is 的患者。此重要发现发表在 2023 年 7 月 25 日的《内科医学年鉴》上，标题为“Comparative Effectiveness of Sodium–Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations”。 （https://www.acpjournals.org/doi/10.7326/M23-0724）。
《内科医学年鉴》论文还油墨未干，中南大学湘雅医院的Guanghua Lei 和 Chao Zeng团队于2023年8月25日在顶级医学杂志JAMA上也发表了一篇论文，标题为“ Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes”。值得注意的是，《内科医学年鉴》论文的两位通讯作者也是JAMA论文的共同作者，说明麻省总医院和湘雅医院是合作关系。 （https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808753#:~:text=Findings%20In%20this%20cohort%20study,initiation%20of%20active%20comparator%20treatments）。这项研究使用英国初级保健数据库, 对2013年1月1日至2022年3月31日期间的痛风和2型糖尿病患者进行了基于人群的回顾性队列研究。研究人员发现，在 5931 名患有痛风和 2 型糖尿病的患者中，和对照组胰高血糖素样肽 1 受体激动剂（GLP-1 RA）或 DPP-4i治疗相比，启动SGLT2i 治疗使痛风复发率减少了 19%，死亡率降低了29%。 此研究结果从另一个角度支持了《内科医学年鉴》论文的结论：SGLT2i 治疗对缓解痛风、减少痛风发作，以及减少痛风并发症，大有益处。
当今世界面临着这么一个严峻的事实：从前号称国王氏病的病，已经越来越流行，1990年时全球仅有2000万成年人患有痛风，但2017年时就已翻番到了4100万。痛风不再只是有钱老男人的富贵病，也成了很多40岁以下年轻人和更年期后妇女的挥之不去的噩梦。不过，痛风虽然无法治愈，但仍可以控制。无论是从安全性还是从治疗成本上考虑，被广泛使用了多年的老药肯定比新药更有吸引力。
有趣的是，我在故事开头提到我举办过的一个party，受邀请的有位朋友是一名位年轻的内分泌科医生，他常常抱怨自己不得不花大量的时间书写病历。如果他碰巧读过本文推荐的两篇论文，说不定他下次抱怨时会三思。总会有一些药物或治疗策略扛得住时间的考验，会从历史数据中脱颖而出。因此，尤其在医学领域，我们必须保留完善的记录，让时间来发现真相。
Gout’s Bliss: Sodium-Glucose Cotransporter-2 Inhibitors Stand out from Historical Data
BackChina Science Lily
Once I invited some friends to my house for dinner. I prepared boiled crab legs, grilled racks of lamb, chilled asparagus, stewed tofu with mushrooms, and red bean slush for dessert. I have also stocked my refrigerator with various types of beers. Some bottled water was also there for those who refuse to indulge themselves. I anticipated that my friends would appreciate my warm hospitality; however, one gentleman about 50 years old, with a slightly plump figure, shook his head with an extremely bitter smile: “I don’t dare to consume anything that you prepared, except for the water.” I immediately realized that this friend must have experienced a gout flare recently, whereas all the food I prepared, including the beer, was purine-rich and will easily elevate his blood urate levels, potentially trigger another attack. Oh, my goodness, I certainly didn’t intend to harm him!
Among thousands of human diseases, gout is one of the few possessing a super long history, with its first identified documentation dating back as early as 2640 BC in ancient Egypt, and with a big name: King’s disease. The name probably originated from the fact that in the past, only kings had the privilege to consume extremely rich foods and unlimited wines. Gout fortunately accompanied many famous people’s lives during their severe pains, including Kublai Khan, Hery VIII, Beethoven, Christopher Columbus, and Benjamin Franklin.
If not combined with other diseases such as diabetes, hypertension, myocardial infarction, or kidney failure, gout alone is typically not life-threatening. But as many have attested, it is truly agonizing, excruciating, and harrowing. The pain that it brings is so piercing and crushing that the patients find it impossible to focus on work or study, fall to asleep, eat properly, and even stand up straight or walk gracefully. The swelling and redness in multiple joints, usually starting from the big toe, may persist for several days to several weeks. The worst of worst, after the traces of damage are completely gone and the patients hope to enjoy a peaceful time, a new flare can strike suddenly and ruin the lives of the affected again.
Gout sufferers will love some recent encouraging news. It is widely known that many gout patients are concomitantly affected with diabetes (you may get an idea by looking at the portraits of Kublai Khan and Hery VIII). A type of medication, sodium-glucose cotransporter-2 inhibitors (SGLT2is), have been used to treat type II diabetes since 2014. Researchers observed that SGLT2is benefit the cardiovascular and renal systems of the diabetic patients and can lower their blood urate levels. Naturally this led to an assumption that SGLT2is may have the potential to prevent or relieve gout. Did the researchers need to conduct animal experiments on little white mice to test the hypothesis? Thank God, no. Instead, the researchers meticulously analyzed tons of historical clinical data. The team led by Hyon K. Choi and Yuqing Zhang from the Division of Rheumatology, Allergy, and Immunology at Massachusetts General Hospital, recently investigated the General Population Database spanning from 1 January 2014 to 30 June 2022 on patients with gout and type 2 diabetes, by using Propensity score–matched and new-user cohort study. These patients were either treated with SGLT2is or dipeptidyl peptidase 4 inhibitors s (DPP-4is), another glucose-lowering agent which has no effect on lowering serum urate levels, at their illness duration. The researchers discovered that patients treated with SGLT2is exhibited significantly fewer recurrent gout flares and experienced much lower rates of myocardial infarction and stroke, as confirmed by the records from emergency department (ED), hospitalization, outpatient visits, and medication dispensing records. This important discovery was published in the Annals of Internal Medicine on 25 July 2023, under the title “Comparative Effectiveness of Sodium–Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations”. (https://www.acpjournals.org/doi/10.7326/M23-0724) .
The ink on the Ann Intern Med paper was still moist when another research group, led by Guanghua Lei and Chao Zeng from the Xiangya Hospital, Central South University, China, published a paper in JAMA on August 25, 2023, with the title “Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes”. Notably, the corresponding authors of the Ann Intern Med paper also served as co-authors on the JAMA paper, demonstrating their collaboration. (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808753#:~:text=Findings%20In%20this%20cohort%20study,initiation%20of%20active%20comparator%20treatments). This study was a population-based retrospective cohort study performed on patients with gout and type 2 diabetes for the period of January 1, 2013 to March 31, 2022, using a UK primary care database. Researchers discovered that among the 5931 patients with gout and type 2 diabetes, initiation of SGLT2i treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality than initiation of active comparators including glucagonlike peptide-1 receptor agonists [GLP-1 RA] or DPP-4i. These research findings can be viewed as a cross-confirmation on the beneficial role of SGLT2i on gout therapies, in alignment with the Ann Intern Med paper’s conclusions.
A harsh reality is that the previous King’s disease is becoming increasingly prevalent worldwide, which affected only 20 million adults globally in 1990, whereas the number has risen to 41 million in 2017. Gout is no longer only rich old man’s disease, but it has also become the nightmares of young populations under 40 years and women post menopause. While gout is not curable, it is still manageable. When considering the safety and cost, older medications that have been already widely used are often more attractive than novel alternatives.
Interestingly, one of the friends I invited, as I mentioned at the beginning of the story, is a young endocrine doctor. He always complains that he spends too much time on medical record-keeping. If he happens to have read those two research papers, he might reconsider his complaints. Some medications or treatment strategies will survive the scrutiny of time and stand out from the historical data. So, particularly in the medical field, it is imperative to maintain thorough records and allow time to reveal the truth.
