Dapagliflozin

Court battles over Medicare drug price negotiations are coming to a head. Two drugmakers are up against deadlines next month to appeal their Inflation Reduction Act challenges to the US Supreme Court. Weeks after that, the first set of negotiated prices under the law is slated to take effect. Legal experts say it’s unlikely the Supreme Court will step in before new prices take effect on Jan. 1 for blockbuster drugs like AstraZeneca’s Farxiga and Bristol Myers Squibb’s Eliquis. But some lower court cases have yet to be resolved, and a high court decision after the fact could still change how the negotiated prices are implemented. “If they get a decision, even a year from now, to preclude these prices from being enforced in the longer term, that’s obviously still a victory for them,” Mintz associate Mitchell Clough told Endpoints News. Drugmakers have been fighting IRA negotiations in court for more than two years, challenging the process on a range of constitutional and statutory grounds. But in every case where judges have ruled on the merits, they’ve sided with the government. AstraZeneca has already appealed its Third Circuit loss to the Supreme Court. Bristol Myers and Johnson & Johnson have Dec. 19 deadlines to file their petitions. And Boehringer Ingelheim, Novo Nordisk and Novartis have deadlines in early January. A handful of these drugmakers have signaled their interest in petitioning the justices. An AstraZeneca spokesperson said their petition was “necessary to support and improve patients’ access to future life-saving medicines, and our rights as a company.” A Novo Nordisk spokesperson said the company is disappointed with its Third Circuit decision and is “assessing our options to appeal this ruling.” Spokespeople for other drugmakers didn’t respond to requests for comment. A spokesperson for trade group PhRMA declined to comment. Clough said drugmakers are likely still looking for a win on their constitutional claims. Meanwhile, the negotiation process has continued. Prices for the second round of negotiations are expected to be announced this week, and CMS is expected to select the next group of drugs for negotiation by Feb. 1. Whether the high court decides to take up the issue will be a pivotal moment, as it could put some of the drugmakers’ constitutional challenges to rest, said Andrew Twinamatsiko, director of the O’Neill Institute’s Center for Health Policy and the Law at Georgetown University. “Depending on how the court decides, there will be a tapering of the broader attacks,” he said. During the first negotiation round , which began in 2023, the government secured discounts of up to 79% off list price on blockbuster drugs. Some pharma companies have argued that the negotiation process unconstitutionally restricts their free speech and due process rights. Some have also challenged CMS’ interpretation of the IRA. For example, Novo Nordisk said CMS’ definition of a “qualifying single source drug” unlawfully allowed the agency to negotiate the price for multiple formulations of its Novolog and Fiasp insulin products. If the drugmakers succeed on some of their statutory challenges, CMS may need to “go back to the drawing board” to reinterpret some parts of the negotiation process, Clough said. A decision like that could affect certain drugs’ eligibility for negotiations, depending on the scope of the opinion and the relief granted, he said. Novo has argued that if CMS had interpreted the statute differently, its products wouldn’t have qualified, at least for the first round of negotiations. Mintz works with some of the drugmakers suing over the IRA, but is not representing them in any of the cases. Whether the Supreme Court will wade into the issue is an open question. Two opposing rulings at the appellate level — also known as a circuit split — would make the high court more likely to take up one or more of the cases, but that hasn’t occurred so far. Some cases have yet to be decided. Industry trade group PhRMA is expected to get a Fifth Circuit decision any day, and Teva recently appealed its case to the DC Circuit. Merck’s case is still working its way through a DC district court. Twinamatsiko said a Fifth Circuit decision in favor of PhRMA could represent a “tectonic shift” in these cases. “As long as the Fifth Circuit decision is pending, anything is possible before Jan. 1,” he said. The absence of a circuit split doesn’t necessarily preclude Supreme Court review. “They have complete discretion in terms of what cases they’re going to take,” Clough said. “They take up all kinds of cases that are not the result of circuit splits every year.” In a dissenting opinion in the J&J and Bristol Myers cases, Third Circuit judge Thomas Hardiman wrote that the IRA “forces the companies to turn over their property to Medicare beneficiaries by threatening them with ruinous excise tax liability” if they chose not to participate. If they had opted out of negotiations, companies would have faced withdrawing from Medicare and Medicaid altogether or paying a steep excise tax. Clough said it’s possible that Hardiman’s dissent could pique the Supreme Court’s interest, as could the “general media interest in the IRA negotiation program.” Whatever the Supreme Court chooses to do, legal experts say they don’t expect litigation challenging the IRA to dissipate completely, particularly as the next rounds come into play. “We knew [litigation] was coming” when the IRA was enacted, said Kristi Martin, a former chief of staff for Medicare who helped craft the agency’s guidance for the first round of negotiations. “That was just part of implementing something like this.”

引言： 在糖尿病及其并发症、代谢相关脂肪性肝病等代谢性疾病领域，多器官损伤的协同防治始终是临床面临的核心挑战。非奈利酮作为新型非甾体类盐皮质激素受体拮抗剂（ns-MRA），凭借精准全面的抗炎抗纤维化作用，已成为2型糖尿病（T2DM）相关慢性肾脏病（CKD）的标准治疗药物。CDS 2025年会上，多项涵盖临床疗效验证、作用机制探索及跨界应用拓展的最新研究集中公布，不仅进一步夯实了其在糖尿病相关CKD领域的核心治疗地位，更揭示了其基于抗炎、抗纤维化的器官保护作用，在心、肾、代谢以及糖尿病视网膜病变（DR）、代谢相关脂肪性肝病（MAFLD）等多系统疾病中的治疗潜力，为心-肾-代谢性疾病（CKM）的综合管理提供了全新思路与循证依据。 一、T2DM相关CKD治疗的疗效与安全性验证 01 单药治疗：明确肾脏保护作用，高钾血症风险可控 郑州大学第一附属医院的研究[1]纳入202例T2DM合并CKD患者，在最大耐受剂量血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体拮抗剂（ARB）的基础上，将患者分为非奈利酮+常规治疗的试验组和仅常规治疗的对照组，干预6个月后，试验组患者尿白蛋白与肌酐比值（UACR）、血浆炎症因子CXCL2水平明显下降（vs.对照组），且血钾、尿素、肌酐等安全性指标与对照组无显著差异，证实其在减少蛋白尿、抑制炎症反应的同时安全性良好。 大连医科大学附属第一医院针对糖尿病相关CKD患者进行的非奈利酮疗效与高钾血症风险因素的回顾性病例分析显示[2]，纳入分析的342例患者中，仅3例（发生率0.88%）发生高钾血症，减量或停药后基本可快速恢复；基线估算肾小球滤过率（eGFR）水平和药物剂量是发生高钾血症的核心相关因素。临床成功应用非奈利酮的关键在于避免在eGFR过低患者中应用以及基于eGFR和血钾监测实施个体化剂量调整。 02 联合治疗：协同增效，拓展适用场景 解放军第九八七医院的单中心RCT研究显示[3]，非奈利酮联合达格列净组（60例）治疗糖尿病相关CKD患者1个月后，临床治疗总有效率显著高于达格列净单药组（60例，P<0.05），肾功能指标（β2微球蛋白、胱抑素C、UACR等）显著更低（P<0.05），左室射血分数（LVEF）更高（P<0.05），同时降低血B型利钠肽（BNP）水平与心血管疾病发生率。这提示，非奈利酮联合达格列净治疗可以改善T2DM相关CKD的心功能，降低心血管疾病发生率。 沈阳市第四人民医院的36例患者研究同样证实[4]，在未应用ACEI或ARB药物治疗的T2DM相关CKD患者[eGFR 30~90 ml/（min·1.73㎡），且UACR>300 mg/g]中，治疗50天后，非奈利酮联合达格列净组UACR降幅大于两药单药治疗组，且未出现高血钾、肌酐明显升高等非预期不良事件。 中西医结合治疗也展现出协同优势。克拉玛依市中西医结合医院的研究[5]纳入180例气阴两虚证糖尿病肾病患者，分别接受非奈利酮或非奈利酮联合“糖尿病肾病膏方”治疗，24周后，两组UACR、中医证候积分均较治疗前显著下降（P<0.01），eGFR下降速度减缓；且联合治疗组UACR降低幅度、中医证候积分改善、eGFR稳定性及总有效率均优于单用单药组。两组不良反应发生率无统计学差异。 二、机制探索：多通路调控，揭示肾脏保护核心机制 广州市红十字会医院的研究通过临床观察与分组实验发现[6]，非奈利酮治疗后，糖尿病肾病患者UACR显著降低，血清及尿液中NLRP3、ASC、Caspase-1等NLRP3炎性体通路标志物水平显著低于标准治疗组（P均＜0.05）。相关性分析显示，血清NLRP3与UACR呈显著正相关（r=0.600, P=0.014），尿ASC与eGFR呈负相关（ r=-0.479, P=0.038），证实非奈利酮可通过调节该炎性通路发挥肾保护作用。 南京医科大学第二附属医院的动物与细胞实验表明[7]，非奈利酮能减轻糖尿病肾病小鼠肾组织病理病变程度，减轻足细胞肿胀、缩小纤维化面积，降低血肌酐（SCr）、尿素氮（BUN）、UACR水平；同时抑制高糖+醛固酮诱导的足细胞上皮间充质转化相关蛋白表达。 上海交通大学医学院附属新华医院的研究揭示[8]，非奈利酮通过抑制盐皮质激素受体（MR）核转位及其与siRNA沉默螺旋家族转录抑制因子 2（Snail2）启动子结合，阻断MR-Snail2通路，从而抑制内皮-间质转分化（EndoMT），缓解糖尿病肾纤维化。 中国人民解放军陆军军医大学第二附属医院的研究通过小鼠单细胞RNA测序发现[9]，足细胞是非奈利酮干预的关键效应细胞，其特异性表达的γ-谷氨酰转肽酶（GGCT）基因在糖尿病肾病中持续下调，且与eGFR显著正相关。非奈利酮治疗可上调GGCT表达，而足细胞特异性GGCT敲除会加重糖尿病肾损伤，包括尿蛋白排泄增加、足突融合加重、肾小球硬化及肾小管间质纤维化加剧。这提示GGCT是非奈利酮介导肾保护作用的重要靶点，参与谷胱甘肽代谢及氧化还原稳态调节，其缺失导致足细胞抗氧化应激能力下降，从而加重足细胞功能障碍。  三、研究拓展：跨界应用潜力，覆盖多系统疾病 01 改善糖尿病视网膜病变（DR） 天津医科大学朱宪彝纪念医院的孟德尔随机化研究发现[10]，CDH2基因在DR发生发展中起到关键作用，非奈利酮可通过抑制CDH2表达延缓DR进展。醛固酮和非奈利酮均能与CDH2紧密结合，体内实验在db/db小鼠视网膜组织中，观察到CDH2表达显著增加，而非奈利酮能降低CDH2表达，这进一步验证了非奈利酮在DR进展中的这一调控关系，为DR治疗提供了新的潜在靶点。 02 干预代谢相关脂肪性肝病 南方医科大学珠江医院的研究构建了两种代谢功能障碍相关性脂肪肝病（MAFLD）小鼠模型[11]，非奈利酮干预后，在代谢功能障碍相关脂肪肝（MAFL）阶段可改善体重、血脂及糖耐量，抑制脂肪酸生物合成通路，分子实验表明MR阻断下调了成脂关键基因并激活脂解通路，从而减轻肝脏脂质蓄积和损伤。在代谢功能障碍相关脂肪性肝炎（MASH）阶段虽未显著改善全身代谢参数，但能缩小脂肪变性面积，脂解通路关键因子表达上调，纤维化标志物表达受到抑制，这表明阻断MR可改善肝脏脂代谢紊乱并延缓纤维化进程，为MAFLD精准治疗提供了新策略。 四、总结 CDS 2025 年会上的系列研究成果，全面彰显了非奈利酮的多维度治疗价值。从临床应用来看，其单药或联合治疗方案在糖尿病相关CKD中展现出显著的心肾保护作用，高钾血症风险可控且可通过个体化剂量调整优化安全性；从机制层面，非奈利酮通过调控NLRP3炎性体通路、阻断MR-Snail2信号、靶向足细胞GGCT基因等多途径发挥作用，为精准治疗提供了坚实的理论支撑；从应用拓展来看，其在DR、MAFLD等糖尿病相关并发症中的跨界潜力，打破了单一疾病治疗的局限，为多器官协同保护提供了新方向。未来随着循证证据的持续积累，非奈利酮有望成为CKM相关疾病的核心药物，为临床实现更全面、精准的疾病管理开辟新路径。 参考文献 （上下滑动可查看） 1.卫芳祎，等. 非奈利酮对2型糖尿病合并慢性肾脏病患者的疗效. CDS 2025. ID: 2187. 2.郭明, 等. 非奈利酮治疗糖尿病肾病的疗效与高钾血症风险因素分析. CDS 2025. ID: 2562. 3.刘彦君, 等. 非奈利酮联合达格列净治疗糖尿病肾病疗效及超声心动图参数、心血管疾病发生率分析. CDS 2025. ID: 922. 4.赵玉蓉.非奈利酮联合达格列净治疗的临床观察. CDS 2025. ID: 3311. 5.吴胜利,等. 非奈利酮联合邓德强糖尿病肾病膏方治疗糖尿病肾病（气阴两虚证）180例临床观察. CDS 2025. ID: 1623. 6.吴丽滢, 等. 非奈利酮对糖尿病肾脏病患者血、尿NLRP3炎性体通路标志物的影响. CDS 2025. ID: 2729. 7.姜凤煊, 等. 盐皮质激素受体拮抗剂非奈利酮阻止高糖及醛固酮诱导的足细胞上皮间充质转化和改善糖尿病肾脏损伤. CDS 2025. ID: 1512. 8.杨柯,等. 非奈利酮通过抑制Snail2介导的内皮-间质转分化缓解糖尿病肾纤维化. CDS 2025. ID: 3024. 9.瞿华, 等. 非甾体类MRA通过调控谷胱甘肽循环酶GGCT改善足细胞损伤及糖尿病肾病. CDS 2025. ID: 1728. 10.刘向阳, 等. 通过可成药基因孟德尔随机化探讨非奈利酮对糖尿病视网膜病变的改善作用及机制. CDS 2025. ID: 3740. 11.刘媛媛, 等. 盐皮质激素受体及其拮抗剂对代谢相关脂肪性肝病脂代谢紊乱的作用研究. CDS 2025. ID: 165. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！ （来源：《国际糖尿病》编辑部） 版权声明 版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。