第150期 - 二甲双胍治疗膝骨关节炎

这是圆桌讨论。

This is the Rounds Table.

好的。

All right.

欢迎各位听众再次收听。

Welcome back, listeners.

这将是一期 solo 嘉宾节目，文章题目是《二甲双胍用于膝骨关节炎》。

This is going to be a solo episode and the article is entitled Metformin for Knee Osteoarthritis.

没错。

That's right.

《超重或肥胖患者使用二甲双胍治疗膝骨关节炎：一项随机对照试验》。

Metformin for knee osteoarthritis in patients who are overweight or obese: a randomized controlled trial.

这篇文章发表于2025年4月的《JAMA》。

This was published in JAMA in April 2025.

简单背景介绍：膝骨关节炎非常普遍。

A quick backdrop, knee osteoarthritis is incredibly common.

结果发现，全球有超过三亿人受此影响。

Turns out it affects more than three hundred million people globally.

这些膝骨关节炎患者中，超过一半是肥胖或超重人群。我之前并不知道这一点，直到读了这项研究，但基础科学研究表明，葡萄糖和脂质代谢异常会促进炎症，从而加剧疾病进展。

More than half of these patients who have knee osteoarthritis are obese or overweight, and basic science studies I didn't know this until I read the study but basic science studies suggest that there's an element of impaired glucose and lipid metabolism which promotes inflammation and can increase disease progression.

我对这一点持怀疑态度，但好吧，既然有基础科学研究显示了这一点，那我就接受吧。

I'm very skeptical of that, but hey, apparently, are basic science studies that show it, so I will buy it.

我们知道，二甲双胍是安全的、廉价的，它能减少肝脏葡萄糖生成，降低胰岛素抵抗，还有其他多种作用。

We know that metformin is safe, cheap, and it reduces hepatic glucose production, reduces insulin resistance among other effects.

因此，这些研究者想知道，二甲双胍是否能帮助超重或肥胖人群缓解骨关节炎？

So these authors wondered, could it help with osteoarthritis among individuals who are overweight or obese?

此前已有观察性研究将二甲双胍与无治疗组进行比较，结果显示二甲双胍能改善骨关节炎，但我并不相信这些研究。

And there have been observational studies that have compared metformin to no treatment and showed that metformin improves osteoarthritis, but I just don't buy those studies.

好的。

Okay.

那么回到这项临床试验，它的设计是怎样的？

So going back to this clinical trial, how was it designed?

这是一项于2021年至2024年在澳大利亚进行的双盲、安慰剂对照试验。

It was a double blind, placebo controlled trial conducted in Australia from 2021 to 2024.

这主要是一项远程试验。

It was primarily a virtual trial.

我可以想象，部分原因是因为新冠疫情。

I got to imagine that was partially because of COVID.

有趣的是，在试验过程中，他们教会患者如何检查膝盖的捻发音、压痛和发热等特征。

And what's kind of interesting is that as part of the trial, they taught patients how to examine their knee for crepitus tenderness and warmth among other features.

纳入的人群是患有症状性膝骨关节炎的成年人。

The included population were adults with symptomatic knee osteoarthritis.

主要的纳入标准包括：年龄40岁及以上，BMI25及以上，膝痛持续至少六个月，且在100毫米视觉模拟量表上的疼痛评分超过40毫米。

So some key inclusion were age, 40 and up, BMI of twenty five and up, a knee pain for at least six months, and pain more than 40 millimeters on a 100 millimeter visual analog scale.

对于这些视觉模拟量表，想象一下一端是0，另一端是100。

So for those visual analog scales, just imagine there's zero on one end, there's a 100 on the other.

你的疼痛在哪里？

Where is your pain?

他们还必须根据美国风湿病学会（ACR）的标准符合膝骨关节炎的诊断。

And they also had to have a neo a based on ACR criteria, American College of Rheumatology.

我不会详细说明这些标准，因为我也不清楚具体内容。

I won't go into those criteria because I don't know what they are.

一些主要的排除标准包括：患有重度骨关节炎、疼痛程度超过80毫米（在0到100毫米的视觉模拟量表上）、计划进行膝关节手术，或患有需要服用二甲双胍等药物的糖尿病。

Some of the key exclusion, if they had severe osteoarthritis, if they had severe pain that was defined as more than 80 millimeters on that visual analog scale ranging from zero to a 100 millimeters, if they had an upcoming knee surgery planned, or if they had diabetes that required medications like, you know, metformin.

此外还有其他排除标准，但我就不多说了。

And then there was other exclusion criteria, but I'll leave it at that.

干预措施是每日服用最高2000毫克的二甲双胍缓释片，对照组为安慰剂；主要结局是六个月后与基线相比视觉模拟量表上疼痛评分的变化，评估由盲法研究助理完成。

The intervention was, metformin extended release up to two thousand milligrams daily compared to was placebo, and the outcome was the change in pain in that visual analog scale at six months compared to baseline, and the outcome was assessed by a blinded research assistant.

结果表明，共有225名患者被招募，其中107人被随机分组。

So the results, two twenty five patients were approached and one hundred and seven were randomized.

平均年龄为59岁。

A mean age was 59.

68%为女性。

Sixty eight percent were female.

典型的BMI为33。

Typical BMI was thirty three.

25%的患者有高血压。

Twenty five percent had high blood pressure.

我首先要指出的是，80%的患者在六个月时完成了主要结局指标。

And I'll just note up front that eighty percent of patients completed the primary outcome measure at six months.

这也意味着18%的患者缺失了主要结局数据。

That also means that eighteen percent were missing the primary outcome.

我还想稍微谈一谈依从性问题。

I also want to talk a little bit about the adherence here.

他们通过患者将药物返还给研究团队来评估依从性，然后研究团队会清点药片数量，以确定患者实际服用了多少药。

So they determined adherence based on patients returning their medications back to the study team, and then the study team would like count pills to see, okay, how many did the patients actually take.

这是临床试验中估算依从性的常见方法。

This is a common approach for estimating adherence in clinical trials.

虽然很不完美，但是一种常见做法。

Very imperfect, but a common approach.

结果发现，只有38%的患者将药物寄回以评估依从性。

And it turns out that, again, only thirty eight percent returned their medications to have adherence assessed.

这意味着另外60%的患者没有寄回，我们完全不知道他们的依从性如何。

That means the other sixty percent did not, and we have no clue what their adherence was like.

因此，在那些寄回药片的人中，研究者估算出服用二甲双胍的依从性为82%，服用安慰剂的为79%。

So among those who, mailed the pills back, they could estimate adherence at eighty two percent with metformin and seventy nine percent with placebo.

好的。

Okay.

关于主要结局指标，在六个月时，视觉模拟疼痛量表的平均变化：二甲双胍组减少了31毫米，安慰剂组减少了19毫米。

So for the primary outcome, at six months, the mean change in the visual analog pain scale, So a reduction in 31 millimeters in the metformin group and a reduction in 19 millimeters in the placebo group.

因此，组间差异约为-11分，对应的标准均数差效应量为0.43。

So a between group difference of, like, you know, minus 11 points corresponding to an effect size with a standardized mean difference of 0.43.

我知道这完全难以理解，但别怪我。

I know that's, like, completely uninterpretable, but don't blame me.

我要怪的是作者们。

I'm blaming the authors.

我也想谈谈不良事件。

I also want to talk about the adverse events.

这并不令人意外，但最常见的不良反应是腹泻，在二甲双胍组中占15%，而在安慰剂组中占8%。

This is unsurprising, but the most common adverse effects were diarrhea at fifteen percent in the metformin group compared to eight percent in the placebo group.

二甲双胍组出现腹部不适的可能性也更高。

The, metformin group also was more likely to have abdominal discomfort.

所以，把这些都综合起来，我先从作者的话说起。

So, you know, putting this all together, first, I'll start with the author's words.

所以，他们讨论部分的开篇句子是这样的。

So their opening sentence of the discussion is this.

在这项基于社区的随机安慰剂对照试验中，患有膝骨关节炎且超重或肥胖的参与者，接受六个月的二甲双胍治疗后，膝关节疼痛和僵硬有所轻度减轻，膝关节功能也有所改善。

In this community based randomized placebo controlled trial, participants with knee osteoarthritis and overweight or obesity, treatment with metformin for six months resulted in a modest reduction in knee pain and stiffness and improvement in knee function.

我对这一点非常怀疑，好吗？

I'm very skeptical of that, okay?

首先，有20%的患者缺失主要结局指标，这可能会削弱研究结果，因为这些患者中可能有一部分之所以没有主要结局数据，是因为他们接受了膝关节手术之类的治疗。

So first off, twenty percent of patients had a missing primary outcome, So that can potentially undermine the findings because maybe a subset of those patients didn't have a primary outcome because they went on to have like a knee surgery, for example.

好吧？

All right?

所以这是这项研究一个非常重要的缺点和局限性。

So that's one really important drawback and limitation of the study.

这项研究的第二个局限性是，只有38%的参与者寄回了药片以评估依从性。

A second limitation of the study is that only thirty eight percent mailed their pills back to assess adherence.

因此，我们真的不知道整体的依从性有多好。

So we really don't know how good the adherence was overall.

最后，我们知道，服用二甲双胍的那组患者出现腹泻的可能性要大得多。

And then finally, we know that the group that got metformin was far more likely to have diarrhea.

因此，这些患者已经破盲了。

So these patients were unblinded.

他们很可能搜索了‘我拉肚子，而我参加的是二甲双胍与安慰剂的试验’，我敢打赌ChatGPT会说：‘你很可能在服用二甲双胍。’

They probably Googled the fact that, hey, I'm having diarrhea and I'm in this trial of metformin versus placebo, and I'm sure ChatGPT then said, okay, you're probably on metformin.

所以，我根本不相信二甲双胍对患有膝骨关节炎的患者会是一个好主意，就这么简单。

So I just don't really buy that metformin is going to be a good idea for patients who have, knee osteoarthritis, full stop.

我也认为还有其他试验。

I also think that there have been other trials.

最相关的是一个针对肥胖并患有膝骨关节炎成人的大规模双盲试验，该试验显示了巨大的效应量。

The most relevant was a large scale double blind trial of semaglutide for adults who had obesity and knee osteoarthritis, and that trial showed a massive effect size.

所以，我还是不认为二甲双胍会是这个患者群体的解决方案。

So, again, I just don't buy that metformin is gonna be the answer in this patient population.

我认为最后的教学要点是，是的，我现在正在授课。

I think a final teaching point and, yes, I am teaching now.

最后一个教学要点是，要有良好的方法来评估随机试验的质量。

A final teaching point is just like having a good approach to evaluate the quality of a randomized trial.

我总结出的一个缩写词是‘phobia’。

And one acronym I've come up with is phobia.

其中的P代表安慰剂对照。

So the p stands for placebo controlled.

好的。

Okay.

因此，这项研究因为采用了安慰剂对照而获得高分。

So this study gets a big point for being placebo controlled.

H 代表资金来源是什么？

H stands for how is it funded?

这项研究由学术机构资助。

This was funded by academia.

O 代表研究结果。

O stands for the outcome.

结果是否相关？

Is it relevant?

数据缺失情况如何？

And how much missingness is there?

那么，研究结果相关吗？

So is the outcome relevant?

我想是的，对吧？

I guess, right?

我觉得患者确实关心膝盖疼痛是否减轻，但主要结局的缺失情况严重吗？

Like I think patients do care about their knee being less painful, but was there a lot of outcome missingness?

答案是肯定的。

And the answer is yep.

有百分之十八的人缺失了主要结局数据。

Eighteen percent of people had a missing primary outcome.

当主要结局的缺失率超过百分之五时，我就开始担心我们能多大程度上依赖这项研究的结果。

And when the primary outcome is missing more than like five percent of the time, I just get a little worried about how much can we rely on the results of the study.

B 代表表面上的盲法。

B stands for blinding on face value.

这是一项双盲试验，但并不是所有双盲试验都能真正对患者保持盲法。

This was a double blind trial, but, you know, not all double blinded trials truly blind the patients.

当你遇到一种常见不良反应时，比如本研究中的药物——二甲双胍引起的腹泻，我认为盲法就会被部分破坏。

And when you have an adverse event, which is like so common with the drug in question, aka in this case, metformin causing diarrhea, then I think you lose some blinding.

I 代表意向性治疗。

I stands for intention to treat.

我不会详细展开这一点。

I won't go into details for that.

A 代表患者数量多、中心数量多。

And a stands for a lot of patients, a lot of centers.

这项研究的患者数量并不多。

And this trial didn't have a lot of patients.

当患者数量不多时，研究结果可能会很脆弱。

And when you don't have a lot of patients, your results can be fragile.

好的。

Alright.

这个单人播客就到这里。

That is it for this solo episode.

我这边进展不错。

Good stuff on my end.

说到骨关节炎，说到普通医学，说到糖尿病——我想是的，毕竟用了二甲双胍，顺带提一下糖尿病试验的数据。

Speaking of osteoarthritis, speaking of general medicine, speaking kind of of diabetes, I guess, with metformin, just plugging diabetes trial files.

这是我们早在至少一年前就开始的热门试验文件。

This has been a popular, trial files that we've started, oh, I don't know, at least a year ago.

当然，原始的试验文件仍在持续进行并不断增长。

And of course the OG trial files is still going strong, continuing to grow.

如果你还没注册，现在就去报名吧。

So sign up for those if you haven't already.

好了，就这样。

All right, that's it.

保重，我们下次再见。

Stay well, and until next time.

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