糖尿病核心更新 2026年3月

我们又迎来了一个出色的论文评审月。

We have another great month of article reviews.

我是尼尔·斯科尼克医生，托马斯·杰斐逊大学西德尼·金梅尔医学院家庭与社区医学系教授。

I'm doctor Neil Skolnik, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University.

和往常一样，和我一起的是我的联合主持人。

And joining me as always is my cohost.

我是约翰·拉塞尔。

I'm John Russell.

我也是托马斯·杰斐逊大学西德尼·金梅尔医学院的家庭与社区医学临床教授。

I'm a clinical professor of family and community medicine also at Sidney Kimmel Medical College at Thomas Jefferson University.

尼尔，今晚能和你一起真是太好了。

Neil, it's great to be with you tonight.

约翰，这又是一组精彩的论文。

And John, this is another set of great articles.

我们先从一篇引人入胜的文章开始，该文章探讨了利用人工智能对基于深度学习的糖尿病视网膜病变检测方法进行真实世界前瞻性验证和经济评估，检测依据为眼底照片。

We're going to start with a fascinating article using AI in real world prospective validation and economic evaluation of deep learning based Diabetic Retinopathy Detection from fundus photographs.

这是一篇发表在《糖尿病护理》上的系统综述和荟萃分析，探讨了这一新兴领域的研究。

And this is a systematic review and meta analysis of kind of this new world area published in Diabetes Care.

接着是一篇关于Orforglipron的文章，这是一种用于治疗2型糖尿病患者肥胖的口服小分子GLP-1受体激动剂，即ATTAIN-2试验。

Then an article on orforglipron, an oral small molecule GLP-one receptor agonist for the treatment of obesity in people with type two diabetes, the ATTAIN-two trial.

这是一项发表在《柳叶刀》上的三期双盲试验。

This was a phase three double blind trial published in The Lancet.

然后我们将讨论美国食品药品监督管理局（FDA）从GLP-1类药物说明书中移除自杀意念警告的事宜。

Then we're going to discuss the removal by the FDA of suicidal ideations for GLP-1s.

接着是一篇题为《根据基线心血管风险评估他汀类药物的有效性与安全性》的文章，这是一项发表在《内科学年鉴》上的目标试验模拟研究。

Then an article titled Effectiveness and Safety of Statins in According to Baseline Cardiovascular Risk, and this was a target trial emulation study in the Annals of Internal Medicine.

我们本月的最后一项研究是《GLP-1受体激动剂与2型糖尿病或心血管代谢疾病患者视神经或视力威胁事件风险的关系》，这是一项发表在《糖尿病护理》上的随机对照试验荟萃分析。

And our final article this month is GLP-one Receptor Agonists and the Risk of Optic Nerve or Vision Threatening Events in Patients with Type two Diabetes or Cardiometabolic Disease, a meta analysis of the randomized controlled trials published in Diabetes Care.

约翰，我们先从这项关于人工智能、真实世界前瞻性验证及经济评估的深度学习研究开始。

John, we're gonna start with that study on AI, real world prospective validation and economic evaluation of deep learning.

以前我觉得深度学习是我们俩在做的事情，但现在它指的是人工智能。

Deep learning was something I used to think you and I did, but now it refers to AI.

基于深度学习的糖尿病视网膜病变检测，使用眼底照片的系统评价与荟萃分析。

Of deep learning based diabetic retinopathy detection from fundus photographs, a systematic review and meta analysis.

我知道我们之前已经讨论过这个话题。

I know this is something we've touched on before.

深度学习在使用眼底照片检测糖尿病视网膜病变方面展现出巨大潜力。

Deep learning has shown a lot of promise for detecting diabetic retinopathy using fundus photographs.

本文旨在通过整合前瞻性验证和经济性证据，评估在不同国家、不同医疗体系中部署基于眼底照片的深度学习糖尿病视网膜病变系统的可行性。

And this article sought to assess the feasibility of implementing deep learning for diabetic retinopathy systems using fundus photographs across different countries, different systems of care by synthesizing prospective validation and economic evidence.

他们检索了五个数据库。

They searched five databases.

研究通过前瞻性评估，考察了诊断性能，并分析了经济性数据。

Studies were prospectively assessed using or looking at diagnostic performance, and they looked at economic analysis.

他们总共纳入了47项研究。

They looked in total at 47 studies.

这项荟萃分析包含了大量信息。

This is a lot of information included in this meta analysis.

而汇总的性能在检测威胁视力的糖尿病视网膜病变时最高。

And the pooled performance was highest in detecting vision threatening diabetic retinopathy.

受试者工作特征曲线下面积为0.974，为了便于理解。

The area under the receiver operating curve was 0.974, just to put that in perspective.

高于0.8被认为是良好的。

Above 0.8 is considered good.

高于0.9被认为是非常好的，意味着具有很高的敏感性和特异性。

Above 0.9 is considered really good, meaning has very good sensitivity and specificity.

次佳的是检测任何糖尿病视网膜病变，其曲线下面积同样非常出色，达到0.959。

The next best at detecting was any diabetic retinopathy where the area under the curve was also frankly fantastic, 0.959.

有15项研究被纳入经济分析，表明在高收入国家这种技术具有成本效益，而在中等收入国家，结果则不一。

15 studies were included in the economic commentary showing that this was cost effective in high income countries, and in middle income countries, the results were mixed.

约翰？

John?

所以，

So,

尼尔，这正是你我长期以来在实践中一直在做的事情。

Neil, this is something that you and I have been doing in our practice for a while.

你知道，如果一个人视网膜的评估仅仅依赖于初级保健诊所拍摄的照片，那会错过很多信息。

You know, I think there's a lot of things that you don't get if the only evaluation of someone's retina is just the photograph taken in the primary care office.

而且这些照片并不总是有效，有时我们会收到反馈说结果无法确定。

And they don't always work, so sometimes we'll get kind of notices back that things are inconclusive.

但对于那些无法就医眼科医生的患者来说，这无疑要好得多。

But certainly this is infinitely better for our patients who do not find their way to the eye doctors.

而且，由于各种原因，越来越多的人未能达到我们建议他们去看眼科医生的标准。

And there is kind of more and more people who, for lots of reasons, just are not meeting the guidelines that we recommend to them to get to the eye doctor.

有趣的是，这种方法在资源更丰富的国家比在资源较少的国家更有意义。

So interestingly enough that this is something that makes most sense in a more resourced country versus a less resourced country.

人们可能会认为，在资源较少的国家，这种方法可能更有必要。

And one would think in a less resourced country that this might make more sense.

我认为它确实能让更多人被纳入评估的范围之内。

I think it is something that does kind of get more people in that area under the curve for being evaluated.

我认为，随着我们越来越多地使用人工智能，我们会看到一些静态图像分析的应用，比如眼底照片、病理切片或X光片的解读。

I think as we are using AI for kind of more and more things, that we are going to see some of the static things that are looking at images, be it a fundus photo, looking at a pathology slide, looking at an x-ray.

我不认为所有事情都会完全由人工智能来完成。

I don't think things will solely be done by AI.

当然，我们需要进行一些质量保证，比如通过复读或双人复核来确保准确性。

Certainly you need some quality assurance being done with some backup reads and double reads.

但对于我们的眼科同行来说，他们可能更应该去做一些更有价值的事情，比如亲自接诊患者或在手术室工作，而不是仅仅查看我们诊室传来的照片。

But for our colleagues who are ophthalmologists, there's probably more good they can be doing, seeing patients live or being in the Operating Room than necessarily just looking at photos from our office.

因此，我认为这是一件令人兴奋的事情。

And so I think that this is an exciting thing.

我认为，尤其是在处理静态图像方面，这类应用会越来越多。

And I think we are going to see more of this happening, especially for things that are static.

接下来的文章来自《柳叶刀》，研究了一种名为orflorvipron的口服小分子GLP-1受体激动剂，用于治疗2型糖尿病患者的肥胖问题。

So our next article is from The Lancet, and it looked at orflorvipron, an oral small molecule GLP-one receptor agonist for the treatment of obesity in patients with type two diabetes.

这是一项三期、双盲、随机、多中心、安慰剂对照的临床试验。

This was a phase three double blind randomized multicenter placebo controlled trial.

这是一项为期72周的III期双盲安慰剂对照试验，覆盖了10个不同国家的136个研究中心。

So this was a 72 phase three double blind placebo controlled trial that was conducted across 136 sites in 10 different countries.

参与者BMI不低于27，糖化血红蛋白在7%至10%之间，他们被随机1:1:1:2分配接受每日口服或氟比普罗恩6毫克、12毫克、36毫克或安慰剂治疗。

Participants had a BMI of twenty seven or greater, an A1c of seven to ten, and they were randomly assigned one to one to one to two to oral daily or florbepron at six milligrams, twelve milligrams, thirty six milligrams, or placebo.

主要终点是基线至第72周体重的平均百分比变化。

The primary endpoint was the mean percent change in body weight from baseline to week seventy two.

主要疗效评估采用意向治疗分析，包括所有随机分配的受试者，无论是否发生中间事件。

Their treatment regimen estimated randomly assigned participants regardless of intercurrent events was the primary estimate.

疗效评估结果作为支持性数据，安全性则在所有接受至少一剂研究药物的患者中进行评估。

And with the efficacy estimate considered supportive, safety was assessed in all patients who were treated with at least one dose of study drug.

这项研究从2023年6月持续到2024年2月。

So this study went from June '3 to February '4.

共有超过2800名参与者接受了筛选。

There were over 2,800 participants screened.

其中1600名患者为女性，占比约为46%。

Sixteen hundred of the patients were female, which would have been met forty six percent.

在剂量递增阶段后，受试者被随机分配接受六毫克、十二毫克、三十六毫克的奥尔弗格利普隆或安慰剂，作为生活方式干预的辅助治疗。

They were randomly assigned following a dose escalation phase to receive either six milligrams of the, or florglipron, twelve milligrams, thirty six milligrams or placebo, as an adjunct to lifestyle modification.

共有1444名患者完成了研究。

Fourteen forty four patients completed the study.

基线体重为101公斤，BMI为35，HbA1c为8%。

The baseline body weight was one hundred and one kilograms with a BMI of thirty five and an A1C of eight.

在治疗期间，从第72周来看，六毫克剂量组的体重平均百分比变化为下降5.1%。

For the treatment regimen period, the mean percentage change in the body weight from week seventy two was a decrease in 5.1% with six milligrams.

估计的治疗差异显示：十二毫克剂量组体重下降7%，三十六毫克剂量组奥尔弗格利普隆的估计治疗差异为下降9.6%，而安慰剂组总体体重下降2.5%。

The estimated treatment difference being a decrease in 2.7, a decrease in 7% with twelve milligrams, and an estimated treatment difference of a decrease in 4.59.6% with the thirty six milligram dose of orflorglipron versus overall a 2.5% decrease with placebo.

所有处方的减重和心血管代谢指标，包括HbA1c，在使用奥尔弗格利普隆后均显著改善。

All prescribed weight and cardiometabolic measures including A1C statistically significantly improved with the orflorglipron.

因不良事件（主要是胃肠道相关）导致的治疗中断在奥尔弗格利普隆组中更为常见。

Treatment discontinuation due to adverse events, mostly GI related, were higher for orflorglipron.

因此，六毫克剂量组的体重下降为6.1%至9%，而安慰剂组为4.1%。

So at the six, the result six point one to nine percent decrease versus placebo four point one percent.

使用或弗格利普隆最常见的不良事件是轻至中度的胃肠道事件，主要发生在剂量递增阶段。

The most common adverse events with the orflorglipron were mild to moderate GI events that would predominantly happen during dose escalation.

研究期间报告了10例死亡，其中6例发生在治疗组，4例发生在安慰剂组。

Ten deaths were reported during the study, six in the treatment group and four were placebo.

研究者认为所有死亡均与研究无关，除了安慰剂组一例和十二毫克或弗格利普隆组一例。

Investigators deemed all deaths unrelated to the study except for one case in the placebo group and one in the twelve milligram orflorglipron group.

对于或弗格利普隆组的病例，未报告与治疗相关的关联。

For the case of the orflorglipron group, no treatment related association was reported.

尼尔？

Neil?

约翰，我认为这是一种非常令人兴奋的药物。

John, I think this is a fantastically exciting medication.

你刚才提到的试验，ATTAIN-2，是ATTAIN-1的补充试验。

So, the trial that you just went over, ATTAIN-two, was the complementary trial to ATTAIN-one.

请记住，所有提交给FDA用于治疗肥胖的药物，都必须在无糖尿病的肥胖人群中进行一项试验，同时在合并糖尿病的肥胖人群中进行另一项独立试验，因为一般来说，在合并糖尿病的肥胖人群中，所有试验的减重效果都会减少约三分之一。

Remember that all medicines that are going to be submitted to the FDA for review for treatment of obesity have to have a trial in people with obesity without diabetes, and a separate trial in people with obesity with diabetes because in general you lose about a third less weight in all of the trials in the people who are in the trials of people with obesity and diabetes.

因此，ATTAIN-one 研究显示，或夫利格龙在超重和肥胖但无糖尿病人群中实现了约11%的体重下降。

So, ATTAIN-one, which was orforglipron in people with overweight and obesity without diabetes, showed a weight loss of approximately 11%.

并且它在代谢参数上的降低和改善与所有GLP-1药物相似。

And it had the same or similar decreases, improvements in metabolic parameters that all the GLP-1s had.

腰围、收缩压、甘油三酯、非HDL胆固醇水平均有所改善，这符合我们的预期。

There were improvements in waist circumference, systolic blood pressure, triglycerides, non HDL cholesterol levels, all improved as we would expect.

你刚才提到的ATTAIN-two研究中的另一点值得注意的是，HbA1c的下降非常显著，降低了1.66%，与ACHieve-one研究中或法格利龙在早期糖尿病患者中的降幅相当。

The other thing in the ATTAIN-two trial, which you just said that's worth noting, is that the decrease in A1C was quite impressive, a decrease of 1.66%, which is in the same range as in the ACHieve one trial, which was orfagliptron in people with early diabetes.

在那项研究中，同样发表于去年的《新英格兰医学杂志》，基线平均HbA1c为8%，接受P1或或GLP-1治疗的患者平均HbA1c下降约1.5%。

In that trial, also in the New England Journal last year, mean A1C was 8%, mean decrease in A1C was one point approximately 1.5% in the P1 or for GLP-one.

这意味着什么？

What does this mean?

这意味着，我们目前拥有一种新型口服药物，它正在接受FDA的加速审查，具有令人振奋的特性。

Well, it means we have a new oral medicine that is currently at the FDA right now as we speak under expedited review that has particular exciting characteristics.

它是一种小分子、非肽类GLP-1受体激动剂。

It is a small molecule, non peptide GLP-one.

为什么这很重要？

Why is that important?

这是因为它的口服吸收率高达百分之七十到八十。

Well, it's important because its absorption orally is in the rate of seventy to eighty percent.

这太棒了。

That's fantastic.

这与口服司美格鲁肽截然不同，后者的吸收率仅有约百分之二到三。

Very different than, for instance, oral semaglutide where the absorption is only about two to 3%.

口服司美格鲁肽，记得几个月前才刚在美国获批上市。

Oral semaglutide, remember, just came a couple of months ago to The United States.

已经获得FDA批准并正式上市。

FDA approved and now has come to market.

它同样是GLP-1类药物中一种出色的口服选择。

Also a fantastic oral option for GLP-1s.

但沃法格利普龙则不同。

Warfagliptron is different, though.

吸收效果好，因此使用起来很方便。

Absorption is good, and therefore it's easy to use.

随餐或用水服用都没有问题。

There are no problems taking it with food or with water.

不需要在一天中的特定时间服用。

It doesn't have to be taken at a particular time of day.

这种化合物在全球范围内的另一个重要意义在于，这与GLP-1的注射剂型尤其不同。

What is also meaningful for this compound worldwide, and this is particularly as opposed to the injectable forms of GLP-1s.

注射剂对温度变化非常敏感。

Injectables are very subject to temperature variation.

在整个供应链的每个环节，它们都必须保持低温，而在世界许多地区，这并不容易做到。

At every point along the supply chain, they have to be kept at a cold temperature, and that is not easy to do in many areas of the world.

小分子非肽类药物没有这些要求，这使得分发变得更容易——这一点我们平时很少考虑。

A small molecule non peptide doesn't have any of those requirements, which makes distribution, which you and I don't think about a lot.

但如果我们考虑到肥胖在全球范围内的严重性以及全球对治疗的需求，这一点就非常重要。

But it's important if we think about how important of a problem obesity is worldwide and the need for therapy worldwide.

因此，它在全球范围内的分发会更容易。

So it's it's gonna be easier for distribution worldwide.

患者外出度假时携带起来也更方便。

It's easier for patients to take on vacation with them.

对于那些不愿接受注射的人，如果这项疗法如这些试验所显示的那样获得FDA批准——很可能获批——它将成为肥胖患者和糖尿病合并肥胖患者的一个绝佳选择。

And for people who prefer not to have an injection, this will if it gets FDA approved as these trials suggest, it likely will, will be an excellent, option for people with obesity and for people with diabetes and obesity.

接下来我们要讨论的是FDA于1月13日发布的一项公告，他们要求从用于肥胖治疗的GLP-1受体激动剂说明书中移除关于自杀行为和自杀意念的警告。

The next piece of information we're gonna discuss is a announcement by the FDA on January 13 that they have requested removal of suicidal behavior and ideation warning from GLP-one agonists for obesity.

请记住，当GLP-1类药物首次获批时，所有肥胖治疗药物都带有这一警告，但用于治疗糖尿病的GLP-1药物从未有过此类警告。

Remember, this was a warning across all medications for obesity when the GLP-1s were first approved, and this has not been a warning on the GLP-1s for diabetes.

这一公告主要是因为FDA进行了非常全面的评估，我们稍后会谈到，该评估并未发现使用GLP-1药物会增加自杀意念或行为的风险。

Basically, this was announced because a very complete FDA evaluation that we'll talk about in a moment did not identify an increased risk of suicidal ideation or behavior with the use of GLP-one medications.

因此，他们要求从药品标签中移除这一警告。

And so that they've requested removal of that from the product label.

正如我所说，在最初获批时，这一警告是统一加在所有口服降糖及减肥药物上的。

As I said, at the time of original approval, was just labeling across all oral glucose rather obesity lowering medications.

那么，FDA是如何得出这个结论的呢？

So, what did the FDA do to come to this conclusion?

他们最初审查了GLP-1的临床试验，发现使用GLP-1治疗肥胖与自杀意念的发生之间没有关联。

Well, they initially reviewed GLP-one clinical trials and found that there wasn't an association between the use of GLP-1s for obesity and the occurrence of suicidal ideation.

但在各个临床试验中，观察到的自杀意念病例数量相对较少，这意味着风险估计存在相当大的不确定性。

But there were a relatively small number of cases of suicidal ideation observed in the individual trials, and that meant there was considerable uncertainty in the risk estimate.

为了解决这一担忧，FDA对所有GLP-1的临床试验进行了全面的荟萃分析，以提高风险估计的精确性。

So to address that concern, the FDA performed a comprehensive meta analysis of all clinical trials across GLP-1s to improve the precision of the risk estimate.

这项荟萃分析包含了91项针对GLP-1药物的安慰剂对照试验，涉及超过10万名患者。

There were 91 placebo controlled GLP-one medication trials in the meta analysis, over 100,000 patients.

而这项荟萃分析再次表明，自杀意念的风险并未增加。

And that meta analysis, again, did not show any increased risk of suicidal ideation.

此外，FDA还利用一个大型管理索赔数据库，开展了一项回顾性队列研究，比较了GLP-1与SGLT2抑制剂在2型糖尿病患者中的使用情况。

And in addition, the FDA conducted a retrospective cohort trial using a large administrative claims database comparing GLP-1s to SGLT2s in people with type two diabetes.

这项研究的人群，约翰，超过了200万人。

That study population, John, was over 2,000,000 people.

我只是想说，当我看到FDA批准的药物是如何被仔细审查的，再想想人们多么轻率地在电视、杂志或社交媒体上推崇那些未经FDA批准的化合物时。

And I just want to say, when I look at how carefully FDA approved medications are examined, and then I think of how people tout non FDA approved compounds and things so lightly off of, you know, on TV or in magazines or social media.

我们甚至去考虑那些未经FDA批准的东西，脑子是不是该检查一下了。

I think our heads should be examined to even think about those non FDA approved things.

因此，FDA对超过200万使用者的研究群体进行了分析，再次发现GLP-1类药物与SGLT2类药物相比，不存在故意自伤风险的增加。

So the FDA then looked at a study population over 2,000,000 users and again found no increased risk of intentional self harm on GLP-1s compared to SGLT2s.

他们在糖尿病患者或肥胖人群的任何亚组中，也都未发现风险增加。

They did not find any increased risk in any subgroup either with diabetes alone or obesity.

他们还审查了已发表的观察性研究和汇总研究，结论一致。

They then also reviewed published observational and pooled studies, same conclusions.

因此，在完成这一全面审查后，建议撤回这一警告。

Therefore, after that comprehensive review, the recommendation to withdraw this warning.

约翰，你的看法呢？

John, your thoughts.

所以，尼尔，我认为对我们听众来说，这个警告被撤回并不会改变他们的行为。

So, Neil, I think for our listeners that this being withdrawn is not going to change what they do.

但这是一个有趣的概念，一种药物上市后。

But it's a kind of an interesting concept in that, a medicine comes out.

回想一下我们职业生涯中的一些药物，比如伐尼克兰，这是治疗烟草成瘾、帮助人们戒烟最有效的药物，曾经一度背负着这种污名，直到FDA最终撤回了警告。

If you think about some of the medicines during our career, varenicline, which is the most effective medicine for treatment of tobacco addiction and helping people get off tobacco, carried this stigma for a while until the FDA actually pulled this.

多西环素。

Doxycycline.

哇。

Wow.

再想想阿维A酸，异维A酸，也带有类似的标签。

If you think about Accutane, isotretinoin, carries some of these things with it.

去年，《柳叶刀》旗下的一本期刊发表了一篇很好的综述文章，研究了哪些类别的药物长期来看真正存在这种问题。

If you look, there was a nice review article last year in one of The Lancet Journals that actually looked to see what categories of medicines actually truly carry this over a long period of time.

排名第一的药物是阿普唑仑。

The number one medicine is going to be alprazolam.

排名第二的是唑吡坦。

Number two is zolpidem.

排在第一位的是用于焦虑或失眠的药物。

It's going to be some of the medicines that are for anxiety or sleepers are category one.

第二位是抗抑郁药，其中包含多种类型的抗抑郁药。

Number two is antidepressants, and there's a wide variety of antidepressants in there.

第三大类是抗癫痫药。

The third kind of major category is anticonvulsants.

以糖尿病为例，有些人可能在使用像加巴喷丁或普瑞巴林这样的药物来治疗神经病变。

So for the context of diabetes, we might have some people who are on something like a GABAKET PET, or a pregabalin or something for some neuropathy.

但我认为要证明因果关系非常困难，因为人们的生活并不一定是线性的。

But I think proving causation is really kind of difficult and people's lives are not necessarily linear.

上世纪60年代初有一位摇滚明星名叫德尔·香农。

There was a rock and roll star from the early 1960s named Del Shannon.

1961年，他有一首冠军单曲叫《Runaway》。

In 1961, he had the number one song in the country called Runaway.

在80年代，氟西汀刚上市时，他因严重的抑郁症开始服用氟西汀。

In the 80s, in the early days of fluoxetine coming out, he was started on fluoxetine for a very severe depression.

在他接受治疗几周后，他自杀身亡，引发了大规模诉讼，最终他的家人对氟西汀的制造商提起的诉讼被驳回。

Several weeks into the course of his therapy, he committed suicide and led to a large lawsuit that was eventually dismissed from his family to the makers of fluoxetine.

因此，很容易就会选择一种药物，你可能更愿意生活在一个有人会告诉你：‘嘿，已经有了一些相关报告’的世界里。

So it becomes very easy to kind of take a medicine and you'd probably rather live in a world where someone's going to say, Hey, there's been some reports of this.

让我们看看两百万人的数据。

Let's look at two million.

让我们看看有两百万人使用过这种药，看看信号是否更明显。

Let's look at two million people who've gotten this to see if the signal is any louder.

我认为药物安全性是一个持续演进的过程。

And I think with med safety, it's in constant evolution.

我认为，当我们听到一些对药物和药品的批评时，人们往往会问：‘他们怎么之前没发现？’

I think sometimes when we are hearing some kind of criticisms of medicine and drugs and things like that, it's, well, how come they didn't know?

如果某种情况只在万分之一的患者中出现，那么在治疗组只有三千人的研究中是无法观察到的。

Well, if something happens, one in ten thousand patients, you're not going to see it in a study that had three thousand people in the treatment arm.

因此，我认为上市后的监测信息才是让我们尽可能安全的关键。

So I think having post marketing information is what allows us to be as safe as we can.

这是我们需要注意的一点，但我们应该能够放心地开具GLP-1类药物，而无需担心自杀意念。

This is something we need to be kind of mindful of, but we should be able to prescribe our GLP-one medicines, without worry about suicidal ideation.

下一篇文章来自《内科学年鉴》。

Next article is from the Ann Intern Med.

这项研究分析了他汀类药物在2型糖尿病患者中的有效性和安全性，依据的是基线心血管风险。

Looked at the effectiveness and safety of statins in patients with type two diabetes according to baseline cardiovascular risk.

这是一项针对英国25至84岁、在2016年2月前确诊为2型糖尿病的参与者的研究。

So this was a study that looked at participants between 25 and 84 years of age in The United Kingdom with a diagnosis of type two diabetes between the years 02/2016.

这些患者无冠状动脉疾病、心肌梗死、中风、心力衰竭、肌病、肝病、风湿性心脏病、精神分裂症或癌症病史。

The patients had no history of CAD, myocardial infarction, stroke, heart failure, myopathy, liver disease, rheumatic heart disease, schizophrenia, or cancer.

患者被分为他汀类药物治疗组与未治疗组，并估算了意向治疗效应的观察性模拟值。

Patients were started on a statin versus non initiation, and they estimated the observational analogs of intention to treat effect.

他汀类药物启动者与未启动者按1:4的比例进行倾向评分匹配，并按Q风险评分的十年预测心血管风险分为三个层级。

Statin initiators were propensity score matched to non initiators in a one to four ratio with a Q risk three strata of ten year predicted cardiovascular risk.

患者根据心血管风险被划分为低风险（低于10%）、中等风险（10%至19%）、高风险（20%至29%）和极高风险（超过30%）。

Patients were stratified as having a low risk of under ten percent, intermediate ten to nineteen percent, high twenty to twenty nine percent, and very high greater than thirty percent.

他们测量了随访十年时全因死亡率和主要心血管死亡、肌病及肝功能障碍的绝对风险差异和风险比。

They measure the absolute risk differences and risk ratios at ten years of follow-up for all cause mortality and major cardiovascular death, as well as myopathy and liver dysfunction.

他们发现，在所有四个风险分层中，他汀类药物的启动都与全因死亡率和主要心血管疾病风险的降低相关。

What they found was statin initiation was associated with reduction in all cause mortality in major cardiovascular disease across all of the strata of risk, the four different categories.

在低风险组中，风险差异和风险比分别显示全因死亡率下降了0.53，风险比降低了20%；主要心血管死亡的风险差异和风险比分别为0.83和0.78。

In the low risk category, the risk difference as well as the risk ratio was a decrease in point five three and the risk ratio was twenty percent lower for all cause mortality, and decrease of zero point eight three and zero point seven eight respectively for major cardiovascular death.

仅在中等风险分层中观察到肌病的轻微增加。

A small increase from myopathy was observed in the moderate risk stratum only.

在所有分层中，均未发现肝功能障碍风险的显著增加。

There was no associated increased risk for liver dysfunction in any of the categories.

尼尔？

Neil?

约翰，我将从两个不同角度来谈谈我对这篇文章的看法。

John, I'm going to approach my thoughts on this article in two different ways.

一是简要评论文章的结论，并将其与美国糖尿病协会当前的推荐和现有数据联系起来。

One is a brief comment on what the article concluded and putting it in context of the ADA's current recommendations and data that's out there.

但我想花几分钟谈谈目标试验模拟研究，这类研究最近越来越常见。

But then I want to talk for a couple of minutes about target trial emulation studies in general, which is something we're seeing a lot more of lately.

请记住，风险差异就是绝对风险降低。

So just realize the risk difference is the absolute risk reduction.

我们通常看到的风险比是相对风险降低。

Risk ratio we're used to seeing is the relative risk reduction.

这里的风险差异为0.5%意味着在十年内，每200人中有一人受益。

Risk difference of point 5% here means that one person out of two hundred over ten years benefited.

但这种益处是重要的。

Now the benefit was important.

它降低了死亡率。

It was decreased mortality.

我们总是需要关注这一点，而不仅仅是说降低了20%。

And it's always important to look at that rather than just say there's a 20% decrease.

因此，作者很好地、清晰地传达了这一点。

So the authors really conveyed that nicely and clearly.

这并不令人意外，对吧？他汀类药物在2型糖尿病患者中是有效的。

This is, it's not a surprise, right, to see that statins work in people with type two diabetes.

美国糖尿病协会（ADA）建议，对于40岁以上的2型糖尿病成人，采用中等强度的他汀类药物进行一级预防。

The ADA recommends moderate intensity statin therapy for primary prevention in adults with type two diabetes who are over 40 years of age.

他们建议，对于具有其他危险因素的患者，可考虑使用高强度治疗。

They recommend high intensity therapy be considered in those with additional risk factors.

这基于大量现有的临床试验。

And this is based on a lot of trials out there.

一项针对超过一万七千名2型糖尿病患者的荟萃分析显示，每降低40毫克/分升的低密度脂蛋白胆固醇，主要血管事件风险约降低20%，而这正是中等强度他汀治疗在通常LDL水平升高人群中所能达到的效果。

There was a meta analysis of over seventeen thousand people with type two diabetes that showed approximately twenty percent reduction in major vascular events for every 40 milligrams per deciliter reduction in LDL cholesterol, which is about what you get with a moderate intensity statin therapy in people with the usual elevated levels of LDL.

虽然已有若干一级预防试验，但这些试验都没有针对心血管风险极低的人群，而这正是本研究试图探索的。

There have been primary prevention trials, but none of those trials looked at people with very low cardiovascular risk, which is what this trial attempted to do.

之所以没有随机试验研究这一人群，是因为要显示获益，试验必须持续非常非常长的时间，或者需要纳入数量极其庞大的受试者。

And the reason no randomized trial looks at that is that the trial would have to last a very, very long time to show a benefit or have to examine a very large number of people.

这适用于观察性研究。

And that's for observational trials.

哎呀，我说错了，应该是观察性研究，约翰。

Oops, I said observational trial, John.

他们称这项研究为目标试验模拟研究。

And they called this a target trial emulation study.

我刚才那样说是个错误吗？

Was that a mistake the way that I said it?

嗯，其实不是。

Well, it wasn't.

我说的是我讨论过目标试验模拟研究。

I said I discussed target trial emulation studies.

多年来，观察性研究和队列研究一直是我们用来研究那些未在前瞻性随机试验中探讨的问题的方法。

For years, observational trials, cohort studies have been what we've used to look at things that are not examined in prospective randomized trials.

我们的数据集变得更加易得。

Our datasets have become more accessible.

它们也变得大得多。

They've become much larger.

这促使真实世界证据成为我们使用的一种重要证据形式。

That's led to the emergence of real world evidence as an important form of evidence that we use.

目标试验模拟研究是一种观察性试验，它预先定义了纳入观察性试验的受试者标准、观察时长以及要考察的参数。

A target trial emulation study is a type of observational trial that defines ahead of time the inclusion criteria for who's going to be included in the observational trial, how long they're going to be looked at, what parameters are going to be looked at.

因此，它试图模仿或模拟随机试验。

So, it tries to mimic or emulate a randomized trial.

但不要被这个花哨的名字迷惑了。

But don't let that fancy name fool you.

它仍然是观察性试验，其主要弱点仍然是混杂变量可能影响结果。

It's still an observational trial and its main Achilles heel remains the potential for confounding variables to affect the outcome.

当思考是否存在潜在的混杂变量时。

And when it comes to thinking, are there likely confounding variables?

这又回到了我们所有人运用批判性分析能力，去判断可能是什么因素。

It comes back to all of us using our critical analytic skills to say what might that be.

坦率地说，我认为这个试验很容易想到一个会推翻结果的混杂变量。

I think of this trial, frankly, it's easy to think of a confounding variable that invalidates the result.

而这个混杂变量是，服用他汀类药物的人风险较低，可能是因为他们由更积极管理所有风险因素的医生照护，或者是因为他们自身更关注健康。

And that confounding variable is that people who are on statins, are on low risk, might be either taken care of by doctors that are more aggressive in taking care of every risk factor they have or might be people who are just more attentive to their own health.

因此，十年后他们的预后更好，这并不令人意外。

And it wouldn't be a surprise that over ten years, they have better outcomes.

所以，我并不反对这样的结论：他汀类药物可能对心血管疾病风险低于通常7.5%或十年风险的人群有益。

So I don't disagree with the conclusion that statins are likely beneficial for people at less than the usual seven point five percent ASCVD risk or ten year risk.

但我认为，我们应谨慎区分目标试验模拟研究——这只是另一种可能含有混杂变量的观察性研究——与真正的前瞻性研究。

But I think we should be careful not to confuse target trial emulation studies, which is just another name for observational trials that might have confanant variables, with real prospective studies.

关于本期的最后一篇文章，我们将探讨发表在《糖尿病护理》上的一篇文章，标题为《GLP-1受体激动剂与2型糖尿病或心血管代谢疾病患者视神经或视力威胁事件的风险》。

For our final article of this month's issue, we're gonna look at an article from Diabetes Care titled GLP-one Receptor Agonists and Risk of Optic Nerve or Vision Threatening Events in Patients with Type two Diabetes or cardiometabolic diseases.

这是一项针对随机对照试验的荟萃分析。

This was a meta analysis of randomized controlled trials.

关于GLP-1受体激动剂与缺血性视神经病变风险之间的关系，目前存在一些相互矛盾的信息。

There's been some conflicting information out there around GLP-one receptor agonist and on the risk of ischemic optic neuropathy.

因此，作者试图综合现有证据，评估GLP-1受体激动剂对2型糖尿病或心血管代谢疾病患者视神经或视力威胁事件风险的影响。

So the authors attempted to synthesize current evidence of GLP-one receptor agonists on the risk of optic nerve or vision threatening events from randomized controlled trials in patients with type two diabetes or cardiometabolic diseases.

他们分析了来自20项已发表的随机试验的超过83,000名参与者。

They looked at a total of over 83,000 participants from 20 published randomized trials.

主要终点是包括缺血性视神经炎、眼缺血综合征、视乳头水肿、失明、视力模糊、视力损害和视力下降在内的视神经或威胁视力的严重不良事件的综合指标。

The primary outcome was a composite of optic nerve or vision threatening serious adverse events, including ischemic optic neuritis, ocular ischemic syndrome, papilledema, blindness, blurred vision, visual impairment, and reduced visual acuity.

在平均约三年的随访期间，GLP-1受体激动剂的使用与主要终点风险增加无关。

Over a mean follow-up duration of approximately three years, GLP-one receptor agonist use was not associated with increased risk of primary endpoints.

其优势比为1.2，但未达到统计学显著性。

There was an odds ratio of one point two, but it did not reach statistical significance.

预先指定的个别不良事件，包括优势比为1.5但置信区间为0.49至4.6的缺血性视神经炎，以及优势比接近1的视力丧失和视觉障碍事件，均与GLP-1使用无显著关联。

Pre specified individual adverse events, including ischemic optic neuritis, which had an odds ratio one point five, but a confidence interval that ranged from 0.49 to 4.6 and vision loss and disturbance events, an odds ratio near one, were not significantly associated with GLP-one use.

约翰？

John?

所以，尼尔，某种程度上

So, Neil, kind of

这很有趣，我认为这与我之前谈到的某种药物与自杀意念相关风险的问题有关。

an interesting thing, and I think this kind of ties into what I talked about earlier about some of the risks with regard to suicidal ideation related to a drug.

再说一遍，我认为这并不是我们每个月在文献中频繁遇到的问题。

Again, I don't think that this is something that is hitting a lot of the literature that you and I are bumping into month over month.

但在准备讨论这篇文章时，我深入查阅了一些关于视力问题的文献。

But in kind of prep for talking about this article, I took a dive into some of the vision literature.

确实，美国验光学会和美国眼科学会都发表过相关论文。

And certainly this is something that there are papers by the American Academy of Optometry and the American Academy of Ophthalmology.

一些专业组织正在对这些药物发出警示信号。

There are signals that are being raised in some of these professional organizations about some of these medications.

我认为这也是一个很好的例子，说明了各种核查与制衡机制的存在，对吧？

And I think that this is also a great example of some of the checks and balances, right?

如果你看一下可能发生的缺血性神经病变，它发生的概率很低，大约每万名患者中有一例。

So if you look at that ischemic neuropathy that can happen, It happens pretty rarely, about one in every ten thousand patients.

所以在规模较小的研究中，人们不太可能经常遇到这种情况。

So not something that someone's going to see very often in kind of a smaller study.

但我认为这项荟萃分析确实令人安心。

But I think this meta analysis is really reassuring.

我认为，最终，不必逐一讨论每一种眼部疾病，总的来说，他们在研究的这八万三千名患者中发现，没有任何人因视力丧失而面临更高的风险。

And I think ultimately, you know, with without kind of going through every different eye condition, at the end of the day, they could say with these eighty three thousand patients that they found that no one was at increased risk of anything that lost their vision.

事实上，总体而言，根据糖尿病患者所处的病程阶段，更好的血糖控制——这与所有GLP-1类药物相关——长期来看将有助于改善视网膜健康和微血管疾病控制。

And in fact, overall, kind of depending on where we are in the course of someone's diabetes, better glycemic control, which is going to be attached to all the GLP-1s, is going to lead long term to better retinal health, better microvascular disease control.

你可能在患者已经出现病变后才注意到，即便如此，研究也表明，无论患者入组时是否已有视网膜病变，其实并没有明显差异。

You might not see it kind of later after someone has already developed that and even they kind of see it that there really wasn't, it really didn't make a difference if someone entered into one of these studies with preexisting retinopathy or not.

所以我认为，至少目前我们听到的信号并不与此相关，这应该能让人安心。

So I think that this should be reassuring that the signal that we're hearing, at least at this point, is really not associated with it.

但他们无法完全排除那些发生率极低的情况。

But they cannot completely rule out things that happen in a very low incidence.

所以再次强调，如果这项荟萃分析包含了八万名受试者，而某种事件的发生率是一百万分之一，

So again, if this meta analysis had eighty thousand people in it and there's something that happens one in a hundred thousand people.

那么这项研究的样本量还不足以捕捉到那些比研究终点更罕见的事件。

The study was not put together enough to pick up kinda all of those events that are more rare than the end that was in the study.

约翰，在我们结束之前，我想提醒所有听众关注我们频道新上线的一档期刊播客，那是《新美国糖尿病协会期刊：糖尿病、肥胖与代谢性心血管护理》的节目，内容非常精彩。

John, before we conclude, I just wanna remind all of our listeners to listen to a new journal podcast that is now on our feed, and that podcast is of the New American Diabetes Association's journal, Diabetes, Obesity, and Cardiometabolic Care, really some fantastic information.

这个月，这个播客将介绍美国糖尿病协会肥胖协会关于超重和肥胖的护理标准，非常精彩的播客。

And this month, that podcast is going over the new ADA's Obesity Association's Standards of Care for Overweight and Obesity, really fantastic podcast.

有关本期讨论的内容，请访问diabetesjournal.org。

Take a discussed in this issue, just go to diabetesjournal.org.

下个月再见，继续收听。

Until next month, keep listening

继续学习。

and keep learning.