痛風患者的福音！老降糖葯從歷史數據中脫穎而出

痛風患者的福音！老降糖葯從歷史數據中脫穎而出

　　倍可親特稿，By Science 專欄作家 Lily / 有一次，我請一些朋友來家吃飯。 我精心準備了煮蟹腿、烤羊排、涼拌蘆筍、蘑菇燉豆腐、和紅豆沙。 我把冰箱塞滿了各種各樣的啤酒，當然，也為那些格外自律的人準備了一些瓶裝水。我以為我的朋友們看到這些食物都會高興壞了，哪知道，一位五十歲左右、身材略顯豐腴的男士卻苦笑著搖了搖頭：「除了水以外，你準備的東西我都不敢碰。」 我立即意識到，這位朋友最近一定是痛風發作了，而我準備的所有食物，包括啤酒，都含有豐富的嘌呤，很容易使他的血尿酸水平升高，從而可能引發下一次痛風發作。天哪，我可沒打算故意放毒害他！

　　在人類的數千種疾病中，痛風是少數幾個擁有超悠久的歷史的一個，它早在公元前2640年的古埃及就有記載。痛風還有一個響亮的名字：國王病。 之所以得此名，可能是因為過去只有國王才有特權享用豐盛的美食和不盡的美酒乃至得痛風。痛風曾幸運地伴隨了諸多名人的痛苦一生，這些名人包括蒙古大汗忽必烈、亨利八世、貝多芬、克里斯托弗·哥倫布、本傑明·富蘭克林等。 其實，如果不合併糖尿病、高血壓、心肌梗塞或腎衰竭等其他疾病的話，痛風通常不致命。但痛風的癥狀，如許多人描述的，簡直痛徹心扉，讓人難以忍受，讓人生無可戀。它的痛有如鋼針穿骨，又有如巨輪碾壓，讓患者寢食難安，無心工作學習，甚至無法直立或行走。疼痛通常從大腳趾外關節開始，然後多個關節都變得又紅又腫又痛，癥狀可能會持續幾天到幾周不等。最糟糕的是，當一切恢復正常，被犯關節完好如初，患者滿以為可以享受些許安寧平靜了，下一次發作可能毫無預警地洶湧而至，再次留下一片狼藉。

　　最近有些讓痛風患者頗感安慰的好消息。眾所周知，許多痛風患者都同時患有糖尿病，你看看大汗忽必烈和亨利八世的肖像，想必你也能猜出幾成。鈉-葡萄糖協同轉運蛋白2抑製劑（SGLT2is）是一種自2014年以來一直被用於治療II型糖尿病的藥物。一些研究人員觀察到，SGLT2is對糖尿病患者的心血管和腎臟系統有保護作用，且能降低患者的血尿酸水平。研究人員自然而然地意識到，SGLT2is 可能能夠預防或緩解痛風。這個設想需要用小白鼠做動物實驗來檢驗嗎？ 謝天謝地，不用。分析海量的歷史臨床數據就夠了。麻省總醫院的風濕過敏和免疫學系的 Hyon K. Choi 和 Yuqing Zhu 團隊，採用傾向性評分匹配和新用戶隊列匹配方法，分析了 2014 年 1 月 1 日至 2022 年 6 月 30 日期間痛風和 2 型糖尿病患者的通用人口資料庫。這些患者在患病期間都接受過 SGLT2is 或二肽基肽酶 4 抑製劑 (DPP-4is) 治療。和SGLT2is相似，DPP-4is 也是一種降糖葯，但對降低血尿酸水平沒有作用，所以正好適合當作對照。 研究人員根據急診記錄 (ED)、住院記錄、門診和配藥等記錄觀察到，接受 SGLT2is 治療的患者痛風複發率顯著降低，心肌梗塞和中風的發生率也明顯低於使用DPP-4is 的患者。此重要發現發表在 2023 年 7 月 25 日的《內科醫學年鑒》上，標題為「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）。

　　《內科醫學年鑒》論文還油墨未乾，中南大學湘雅醫院的Guanghua Lei 和 Chao Zeng團隊於2023年8月25日在頂級醫學雜誌JAMA上也發表了一篇論文，標題為「 Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes」。值得注意的是，《內科醫學年鑒》論文的兩位通訊作者也是JAMA論文的共同作者，說明麻省總醫院和湘雅醫院是合作關係。 （https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808753#:~:text=Findings%20In%20this%20cohort%20study,initiation%20of%20active%20comparator%20treatments）。這項研究使用英國初級保健資料庫, 對2013年1月1日至2022年3月31日期間的痛風和2型糖尿病患者進行了基於人群的回顧性隊列研究。研究人員發現，在 5931 名患有痛風和 2 型糖尿病的患者中，和對照組胰高血糖素樣肽 1 受體激動劑（GLP-1 RA）或 DPP-4i治療相比，啟動SGLT2i 治療使痛風複發率減少了 19%，死亡率降低了29%。 此研究結果從另一個角度支持了《內科醫學年鑒》論文的結論：SGLT2i 治療對緩解痛風、減少痛風發作，以及減少痛風併發症，大有益處。

　　當今世界面臨著這麼一個嚴峻的事實：從前號稱國王氏病的病，已經越來越流行，1990年時全球僅有2000萬成年人患有痛風，但2017年時就已翻番到了4100萬。痛風不再只是有錢老男人的富貴病，也成了很多40歲以下年輕人和更年期後婦女的揮之不去的噩夢。不過，痛風雖然無法治癒，但仍可以控制。無論是從安全性還是從治療成本上考慮，被廣泛使用了多年的老葯肯定比新葯更有吸引力。

　　有趣的是，我在故事開頭提到我舉辦過的一個party，受邀請的有位朋友是一名位年輕的內分泌科醫生，他常常抱怨自己不得不花大量的時間書寫病歷。如果他碰巧讀過本文推薦的兩篇論文，說不定他下次抱怨時會三思。總會有一些藥物或治療策略扛得住時間的考驗，會從歷史數據中脫穎而出。因此，尤其在醫學領域，我們必須保留完善的記錄，讓時間來發現真相。

　　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.