Differences are starting to emerge among the weight-loss and diabetes drugs targeting the GLP-1receptor.Credit: Michael Siluk/UCG/Universal Images Group/Getty

针对GLP-1受体的减肥和糖尿病药物之间开始出现差异。提供者：迈克尔·西卢克/加州大学政府/环球影业集团/盖蒂

A host of drugs that cause impressive weight loss has transformed the treatment of obesity — and given consumers an unprecedented choice of therapies for slimming down. Now, research is beginning to reveal how these drugs might differ from one another, despite functioning in similar ways.Semaglutide, tirzepatide and other recently developed drugs for treating obesity and metabolic disorders all work in part by mimicking a natural hormone called glucagon-like peptide-1 (GLP-1).

一系列能显著减肥的药物改变了肥胖症的治疗方法，并为消费者提供了前所未有的减肥疗法选择。现在，研究开始揭示这些药物之间的差异，尽管它们的功能相似。Semaglutide、tirzepatide和其他最近开发的治疗肥胖和代谢紊乱的药物都部分通过模仿一种称为胰高血糖素样肽-1（GLP-1）的天然激素起作用。

But studies have found that the drugs vary in their ability to prevent conditions such as type 2 diabetes1, and that some cause greater weight loss than others2. There are also differences between these drugs and an older generation of GLP-1 medications, with research hinting that some of the earlier drugs could be more effective against neurodegenerative conditions such as Parkinson’s disease3 than later drugs.Understanding the differences might help physicians to better tailor treatments, says Beverly Tchang, an endocrinologist at Weill Cornell Medicine in New York City.

但研究发现，这些药物预防2型糖尿病等疾病的能力各不相同，有些药物比其他药物导致更大的体重减轻2。这些药物与老一代GLP-1药物之间也存在差异，研究表明，一些早期药物可能比晚期药物更有效地治疗帕金森病等神经退行性疾病3。了解这些差异可能有助于医生更好地定制治疗方法，纽约市威尔康奈尔医学院的内分泌学家贝弗利·张说。

“For example, if someone with obesity has cardiovascular disease, I am tending to reach first to semaglutide, more than tirzepatide, because we have the data,” she says, referring to a study4 that showed that semaglutide cuts the risk of severe cardiovascular events in people with such conditions. But the choice might be different for someone with sleep apnea, she says, citing a study5 in which tirzepatide reduced sleep apnea symptoms in people with obesity.Head-to-head comparisonAmong the bestselling weight-reducing drugs are semaglutide, sold as Ozempic and Wegovy, and tirzpeatide, sold as Mounjaro and Zepbound.

她说：“例如，如果肥胖者患有心血管疾病，我倾向于首先使用semaglutide，而不是tirzepatide，因为我们有数据，”她指的是一项研究4，该研究表明semaglutide可以降低患有此类疾病的人发生严重心血管事件的风险。但对于患有睡眠呼吸暂停的人来说，选择可能会有所不同，她说，她引用了一项研究5，在该研究中，tirzepatide可以减轻肥胖人群的睡眠呼吸暂停症状。头对头比较Namong最畅销的减肥药是semaglutide，以Ozempic和Wegovy的形式销售，以及tirzpeatide，以Mounjaro和Zepbound的形式销售。

A study published this month1 found that tirzepatide is better than semaglutide at preventing the development of typ.

本月1日发表的一项研究发现，在预防typ的发展方面，tirzepatide优于semaglutide。

Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective

超越Ozempic：全新的肥胖药物将更便宜、更有效

Both semaglutide and tirzepatide mimic GLP-1, which is involved in blood sugar regulation and appetite suppression. This mimicry allows the drugs to activate receptors that are normally activated by GLP-1.Tirzepatide also mimics another hormone called gastric inhibitory polypeptide (GIP), which plays a part in fat metabolism.

semaglutide和tirzepatide都模拟GLP-1，GLP-1参与血糖调节和食欲抑制。这种模拟使药物能够激活通常由GLP-1激活的受体。替利帕肽还模拟另一种称为胃抑制多肽（GIP）的激素，它在脂肪代谢中起作用。

As a result, tirzepatide activates receptors normally activated by both GLP-1 and GIP.But it’s an oversimplification to assume that tirzepatide’s apparent higher potency is because it targets two hormones instead of one, says Tchang. Tirzepatide “doesn’t activate the GLP-1 and GIP receptors equally”, she says.

。但是，Tchang说，假设替罗西肽明显更高的效力是因为它针对两种激素而不是一种激素，这过于简单化了。她说，Tirzepatide“不能同样激活GLP-1和GIP受体”。

Instead, the drug binds more effectively with the GIP receptor than with the GLP-1 receptor. One hypothesis is that tirzepatide’s GIP activity boosts GLP-1-induced weight loss, even though its GLP-1 receptor activation is weaker.An experimental drug being developed by biotechnology company Amgen, based in Thousand Oaks, California, also targets receptors for both GLP-1 and GIP.

相反，该药物与GIP受体的结合比与GLP-1受体的结合更有效。一种假设是，尽管其GLP-1受体激活较弱，但替罗西肽的GIP活性可促进GLP-1诱导的体重减轻。总部位于加利福尼亚州千橡树市的生物技术公司Amgen正在开发一种实验药物，该药物也针对GLP-1和GIP的受体。

But this drug, unlike tirzepatide, doesn’t activate GIP receptors. Instead, it blocks the receptors. The medication had promising weight-loss results in an early clinical study6.Scientists are now trying to reconcile why marked weight loss is achieved both from activating the GIP and GLP-1 receptors and from activating the GLP-1 receptors and blocking the GIP receptors.

但这种药物与替罗西肽不同，不会激活GIP受体。相反，它会阻断受体。该药物在早期的临床研究中取得了令人鼓舞的减肥效果6。科学家现在正在试图调和为什么通过激活GIP和GLP-1受体以及激活GLP-1受体和阻断GIP受体都可以实现明显的体重减轻。

“There are theories and people are working on this, but I think we should be a little humble and admit that there are still things we don’t fully understand,” says Daniel Drucker, an endocrinologist at the University of Toronto in Canada.Saving the brainGLP-1 drugs not only cause weight loss but also tame inflammation, which might partially explain why they have shown potential for slowing down neurodeg.

加拿大多伦多大学内分泌学家丹尼尔·德鲁克（DanielDrucker）说：“有理论和人们正在对此进行研究，但我认为我们应该谦虚一点，承认还有一些事情我们没有完全理解。”。拯救大脑GLP-1药物不仅可以减轻体重，还可以抑制炎症，这可能部分解释了为什么它们显示出减缓neurodeg的潜力。

Anti-obesity drugs’ side effects: what we know so far

抗肥胖药物的副作用：我们目前所知

Some researchers think that the better a GLP-1 drug penetrates the brain, the better it might be at treating neurodegenerative diseases. So far, it’s not clear how far into the brain these drugs travel, but animal studies7 suggest differences between the GLP-1 medications in that regard.Exenatide, for example, seems to cross the blood–brain barrier, a protective shield that controls which substances can enter the brain from the bloodstream.

一些研究人员认为，GLP-1药物穿透大脑的效果越好，它可能更好地治疗神经退行性疾病。到目前为止，尚不清楚这些药物进入大脑的程度，但动物研究7表明GLP-1药物在这方面存在差异。例如，艾塞那肽似乎穿过血脑屏障，这是一种保护屏障，控制哪些物质可以从血流进入大脑。

Christian Hölscher, a neuroscientist at the Henan Academy of Innovations in Medical Science in Zhengzhou, China, attributes the medication’s initial success in treating Parkinson’s disease to that ability.He notes that a version of exenatide that was modified to last longer in the blood did not have the same success in treating Parkinson’s as the original version8.

中国郑州河南省医学科学创新研究院的神经科学家克里斯蒂安·赫尔舍尔（ChristianHölscher）将该药物治疗帕金森病的初步成功归因于这种能力。他指出，一种经过改良的艾塞那肽在血液中持续时间更长，但在治疗帕金森氏症方面并没有像最初的艾塞那肽那样成功。

The modified version is a much larger molecule that cannot get into the brain. “That really shows how important it is to get the drug into the areas where the damage is if you want to improve and protect the neurons,” he says. He also notes that studies suggest that semaglutide cannot cross the blood–brain barrier.

修改后的版本是一个更大的分子，不能进入大脑。他说：“这确实表明，如果你想改善和保护神经元，将药物注入受损区域是多么重要。”。他还指出，研究表明，semaglutide不能穿过血脑屏障。

“So, the newest drugs on the market for diabetes are very unlikely to show very good effects in Alzheimer’s or Parkinson’s.”But other researchers don’t share this opinion. “I don’t think we have very good data correlating brain penetration with activity in neurodegenerative disease,” says Drucker..

“因此，市场上用于治疗糖尿病的最新药物不太可能对阿尔茨海默氏症或帕金森氏症显示出很好的效果。”但其他研究人员不同意这一观点。德鲁克说：“我认为我们没有很好的数据将大脑渗透与神经退行性疾病的活动联系起来。”。。