Most powerful obesity drug yet: People lost up to 25% of weight in trial
Most powerful obesity drug yet: People lost up to 25% of weight in trial
迄今最强减肥药：临床试验显示受试者体重减轻高达 25%
Researchers published late-stage clinical trial data today for the latest obesity drug, retatrutide—expected to be the most powerful formula yet—and the results appear in line with high expectations. Patients with obesity on the highest retatrutide dose lost an average of 25 percent of their body weight after 80 weeks, and an average of 30 percent after an extension period to 104 weeks. Overall, more than a third of participants taking retatrutide lost 30 percent or more of their weight. 研究人员今日公布了最新减肥药物 retatrutide 的后期临床试验数据。该药被预期为迄今最强效的配方，试验结果也符合人们的高期望。在接受最高剂量 retatrutide 治疗的肥胖患者中，80 周后平均体重减轻了 25%，在延长至 104 周的观察期后，平均减重达到 30%。总体而言，超过三分之一服用 retatrutide 的参与者减重幅度达到或超过了 30%。
The drug also proved effective at reducing knee pain (by up to 62 percent) in a subset of participants with obesity-linked knee osteoarthritis. It reduced the number of sleep apnea events per hour (by up to 57 percent) in a subset of participants with obesity-linked obstructive sleep apnea. The drug improved cardiometabolic measurements across the board, including blood pressure, triglycerides, and low-density lipoprotein cholesterol (bad cholesterol). At the start, more than a third of trial participants had prediabetes and, by the end, the condition had resolved in more than 90 percent of those participants. 该药物在患有肥胖相关膝骨关节炎的受试者亚组中，被证明能有效减轻膝盖疼痛（最高达 62%）。在患有肥胖相关阻塞性睡眠呼吸暂停的受试者亚组中，它减少了每小时睡眠呼吸暂停的次数（最高达 57%）。该药全面改善了心脏代谢指标，包括血压、甘油三酯和低密度脂蛋白胆固醇（坏胆固醇）。试验开始时，超过三分之一的参与者患有糖尿病前期，而到试验结束时，其中超过 90% 的参与者的病情得到了缓解。
The trial began in 2023 and included 2,339 participants from 131 clinical trial sites in 11 countries. Participants were broken into four nearly equal groups, given either: 4 mg of retatrutide, 9 mg, 12 mg, or a placebo. Across all groups, the average starting weight was around 113 kg (250 pounds), and the average body mass index (BMI) was 40. For the subset analyses, 574 participants had knee osteoarthritis, and 243 had obstructive sleep apnea. The results appeared today in the New England Journal of Medicine. 该试验于 2023 年开始，涵盖了 11 个国家 131 个临床试验点的 2,339 名参与者。参与者被分为四个几乎相等的小组，分别接受 4 毫克、9 毫克、12 毫克的 retatrutide 或安慰剂。在所有小组中，平均起始体重约为 113 公斤（250 磅），平均体重指数 (BMI) 为 40。在亚组分析中，574 名参与者患有膝骨关节炎，243 名患有阻塞性睡眠呼吸暂停。研究结果今日发表在《新英格兰医学杂志》上。
The data is likely to only ratchet up the anticipation for the drug among the millions of Americans with obesity. Retatrutide has been so sought after that, in June, news broke that top health officials in the Trump administration were involved in granting special access to the experimental medicine to a mystery 79-year-old in April—widely speculated to be Trump, who was 79 at the time. 这些数据很可能会进一步加剧数百万美国肥胖患者对该药物的期待。Retatrutide 备受追捧，以至于今年 6 月有新闻爆出，特朗普政府的高级卫生官员曾于 4 月参与为一名神秘的 79 岁人士提供该实验性药物的特殊使用权——外界普遍猜测此人正是当时 79 岁的特朗普。
Next-generation obesity drug Retatrutide is being developed by pharmaceutical giant Eli Lilly, which also makes tirzepatide, a potent dual-acting treatment for obesity (Zepbound) and type 2 diabetes (Mounjaro). Both medications build on GLP-1-based obesity drug semaglutide (Ozempic/Wegovy) from pharmaceutical company Novo Nordisk. Tirzepatide targets not just GLP-1 (aka Glucagon-like peptide-1), but also GIP (aka glucose-dependent insulinotropic polypeptide). Retatrutide builds on these drugs by adding glucagon to the combination of GLP-1 and GIP. 下一代减肥药 Retatrutide 由制药巨头礼来公司 (Eli Lilly) 开发，该公司还生产替尔泊肽 (tirzepatide)，这是一种用于治疗肥胖症 (Zepbound) 和 2 型糖尿病 (Mounjaro) 的强效双重作用药物。这两种药物均建立在诺和诺德公司 (Novo Nordisk) 基于 GLP-1 的减肥药司美格鲁肽 (Ozempic/Wegovy) 的基础之上。替尔泊肽不仅针对 GLP-1（胰高血糖素样肽-1），还针对 GIP（葡萄糖依赖性促胰岛素多肽）。Retatrutide 在这些药物的基础上，将胰高血糖素 (glucagon) 加入到 GLP-1 和 GIP 的组合中。
All three are hormones that have overlapping roles in responses to food, helping the body regulate blood sugar levels, the feeling of fullness, how much we eat, and downstream metabolic factors. The interplay among the three hormones is complex, and they have different activities in different places in the body and at different times. 这三种激素在对食物的反应中具有重叠的作用，帮助身体调节血糖水平、饱腹感、进食量以及下游的代谢因素。这三种激素之间的相互作用非常复杂，它们在身体的不同部位和不同时间具有不同的活性。
GIP is secreted by cells (K cells) in the first sections of the small intestine, right after the stomach. This hormone is best known for stimulating insulin release in response to glucose (sugar). But GIP has other activities, including triggering the degradation of triglycerides (a type of fat in the blood) and working in the brain to trigger the feeling of being full. It also has a role when blood glucose levels get too low. In that case, GIP stimulates an increase in glucagon. GIP 由胃部之后的小肠前段细胞（K 细胞）分泌。这种激素最广为人知的作用是响应葡萄糖（糖）刺激胰岛素释放。但 GIP 还有其他活性，包括触发甘油三酯（一种血液中的脂肪）的降解，并在大脑中触发饱腹感。当血糖水平过低时，它也发挥作用。在这种情况下，GIP 会刺激胰高血糖素的增加。
Glucagon is a hormone released from alpha cells in the pancreas, and it acts counter to some of the main roles of GIP and GLP-1. Glucagon is best known for triggering the release of glucose and fatty acids into the blood, which it does when blood sugar levels get too low (hypoglycemia). But after meals, glucagon also seems to play a role in increasing insulin production, delaying stomach emptying, and regulating lipid levels. 胰高血糖素是由胰腺中的 α 细胞释放的一种激素，它的作用与 GIP 和 GLP-1 的一些主要功能相反。胰高血糖素最广为人知的作用是触发葡萄糖和脂肪酸释放到血液中，这通常发生在血糖水平过低（低血糖）时。但在餐后，胰高血糖素似乎也在增加胰岛素产生、延缓胃排空和调节脂质水平方面发挥作用。
GLP-1, the most famous of the hormones, is produced by cells (L cells) further down the gastrointestinal tract, namely at the end of the small intestine (the ileum) and the colon. GLP-1 works in response to sugar to increase the release of insulin. It delays stomach emptying and works in the brain to trigger the feeling of being full. It can also send signals to spur the degradation of lipids in fat tissue. Additionally, both GLP-1 and GIP can stimulate the release of another hormone, called adiponectin, which can help with insulin sensitivity and reduce inflammation. GLP-1 是这些激素中最著名的一种，由胃肠道更下方的细胞（L 细胞）产生，即小肠末端（回肠）和结肠。GLP-1 通过响应糖分来增加胰岛素的释放。它能延缓胃排空，并作用于大脑以触发饱腹感。它还可以发送信号来促进脂肪组织中脂质的降解。此外，GLP-1 和 GIP 都能刺激另一种名为脂联素 (adiponectin) 的激素释放，这有助于提高胰岛素敏感性并减少炎症。
Trial limitations
试验局限性
Retatrutide can stand in for all three hormones (GLP-1, GIP, and glucagon), but its active ingredient is a single synthetic peptide. Different sections of the molecule interact with the specific receptors for each of the three hormones, playing the role of the hormones. However, it doesn’t bind to these receptors with the same strength as the natural hormones; compared to GLP-1 and glucagon, retatrutide is less potent, but compared to GIP, the drug is nearly nine times more potent. The peptide is also stabilized, so it stays active in the blood for six days, allowing for weekly injections. Retatrutide 可以替代所有这三种激素（GLP-1、GIP 和胰高血糖素），但其活性成分是一种单一的合成肽。该分子的不同部分与这三种激素各自的特定受体相互作用，从而发挥激素的作用。然而，它与这些受体的结合强度不如天然激素；与 GLP-1 和胰高血糖素相比，retatrutide 的效力较低，但与 GIP 相比，该药的效力高出近九倍。这种肽还经过了稳定化处理，因此可以在血液中保持六天的活性，从而实现每周一次的注射。
The effects of the triple-acting drug seem more potent than in the previous obesity drugs. But a notable limitation of the trial is that it didn’t compare retatrutide to an existing treatment, such as tirzepatide. How it compares in weight loss and other health benefits will need to be explored in future trials. So far, retatrutide’s safety looks similar to what’s seen with existing GLP-1 and GLP-1/GIP drugs: The most common complaints were transient, mild-to-moderate gastrointestinal symptoms, such as nausea, diarrhea, and constipation. Some participants reported feeling dizzy and having low blood pressure on retatrutide, which was more common among people taking medication for high blood pressure. Ten people in the trial had cardiovascular events (including one in the placebo group), and there were also 10 reports of pancreatitis. 这种三效药物的效果似乎比之前的减肥药更强。但该试验的一个显著局限是，它没有将 retatrutide 与现有的治疗方法（如替尔泊肽）进行比较。它在减重和其他健康益处方面如何对比，需要在未来的试验中进行探索。到目前为止，retatrutide 的安全性看起来与现有的 GLP-1 和 GLP-1/GIP 药物相似：最常见的抱怨是短暂的、轻度至中度的胃肠道症状，如恶心、腹泻和便秘。一些参与者报告在使用 retatrutide 后感到头晕和低血压，这在服用高血压药物的人群中更为常见。试验中有 10 人出现了心血管事件（包括安慰剂组中的 1 人），此外还有 10 例胰腺炎报告。