Ziltivekimab

先天免疫系统激活所诱发的慢性全身性炎症，是推动慢性肾脏病进展、继发动脉粥样硬化及心血管疾病的核心因素。过去15 年间，直接靶向炎症通路成为新兴研究方向，旨在降低慢性肾脏病患者的动脉粥样硬化性心血管疾病风险、延缓肾病进展，目前该领域研究仍在积极开展。现阶段针对肾病患者开展及推进中的临床试验，主要靶向白介素- 1、白介素 - 1 受体、白介素 - 6、白介素 - 6 受体、NLRP3 炎症小体、核因子红细胞 2 相关因子 2以及衰老清除剂。在等待各项Ⅲ 期临床试验结果的同时，抗炎细胞因子疗法在科研探索与临床落地层面，仍面临诸多挑战与亟待考量的问题。 👩🎓 引言 炎症是物种演化过程中保留下来的生理机制，在机体遭受损伤与感染时，对生存起到关键保护作用[1]。但受社会、心理、环境及生物等多重因素影响，炎症由急性转为慢性后，会扰乱机体正常生理功能，提升各类慢性病的发病风险[1]。本篇综述将梳理慢性肾脏病（CKD）患者体内慢性全身性炎症的相关证据，阐明其与动脉粥样硬化病变、心血管高风险及肾病进展的关联；同时结合已完成及正在开展的临床试验，介绍靶向慢性肾脏病相关慢性炎症的新型治疗药物。 👩🎓 一、慢性肾脏病中的慢性炎症与炎症小体 先天免疫系统激活引发的无菌性炎症，是慢性肾脏病发生、进展以及继发动脉粥样硬化性心血管疾病（ASCVD）的重要驱动因素，该过程部分依赖NLRP3（NLR 家族吡啶结构域蛋白 3）炎症小体的活化（见图1）[2,3]。 肾脏是维持免疫系统稳态的重要器官，可清除体内细胞因子与细菌抗原，但同时肾脏组织也极易受到促炎细胞因子的损伤[4]。NLRP3 炎症小体是位于细胞质内的多蛋白复合物，可激活半胱天冬酶，是先天免疫系统的核心组分[5]。该复合物主要表达于巨噬细胞等免疫细胞，活化后会促使白介素- 1β（IL-1β）、白介素 - 18（IL-18） 等促炎细胞因子释放，进而诱发肾脏炎症、造成肾损伤[5,6]，同时推动动脉粥样硬化病变发展[7]。基因编辑小鼠模型研究证实，NLRP3 介导的促炎细胞因子释放并非伴随现象，而是直接参与慢性肾脏病进展与动脉粥样硬化性心血管疾病发病的关键环节[6,7]。此外，白介素 - 6（IL-6）作为一种促炎细胞因子，是炎症反应中调控作用极强的介质，同样会促进慢性肾脏病及其并发症（动脉粥样硬化性心血管疾病）的进展[8]。 👩🎓 二、慢性全身性炎症：参与慢性肾脏病进展、诱发新发肾病 已有充分研究证实：随着估算肾小球滤过率（eGFR） 下降、肾功能不断减退，患者体内慢性全身性炎症的发生率与严重程度同步升高。外周血中白介素- 1β、白介素 - 1 受体拮抗剂（IL-1RA）、白介素 - 6、超敏 C 反应蛋白（hs-CRP） 等标志物水平均可印证这一规律[9-12]，这也说明慢性肾脏病本质属于低度慢性炎症性疾病。 慢性炎症可通过扰乱肾脏微循环调节、影响肾脏灌注、加重氧化应激、最终诱导肾纤维化等机制，推动慢性肾脏病持续进展[13]。慢性肾功能不全队列研究（CRIC）结果显示，对于慢性肾脏病患者，外周血白介素 - 6 等炎症因子水平升高，会显著增加肾脏不良终点事件的发生风险[14]。 在普通成年人群中，炎症标志物升高也可预测肾功能减退与新发慢性肾脏病。例如心血管健康研究发现，社区老年人群体内C 反应蛋白水平偏高，与肾功能下降速度加快独立相关[15]。另一项纳入约 5000 名成年人的人群队列研究显示，基线外周血白介素 - 6 水平升高，可独立预测随访 15 年间新发慢性肾脏病的风险[16]。 👩🎓 三、炎症在动脉粥样硬化病变中的作用 除加速肾病进展外，慢性全身性炎症也是慢性肾脏病患者发生动脉粥样硬化性心血管疾病的核心诱因。CRIC 研究纳入2399 名基线无动脉粥样硬化性心血管疾病病史的受试者，为期 7 年的随访结果显示：白介素- 6、肿瘤坏死因子 -α 及综合炎症评分等炎症标志物，与动脉粥样硬化性心血管疾病、全因死亡风险独立相关；联合炎症标志物与肾功能指标后，对心血管风险的预测效能优于传统危险因素[17]。 Darapladib Therapy (STABILITY)试验纳入超14000 名慢性冠心病患者，结果显示：无论患者估算肾小球滤过率处于何种水平，外周血白介素 - 6 升高均与远期主要不良心血管事件（MACE）、死亡风险相关；其中估算肾小球滤过率＜60 mL/min/1.73m² 的患者风险最高。此外，基因学研究也证实，白介素- 6 受体基因位点、NLRP3 基因位点与心血管不良结局存在关联[20]。 大量证据表明，在慢性肾脏病患者中，巨噬细胞内除低密度脂蛋白外，其他因素也会诱发炎症性动脉粥样硬化。多项他汀类药物临床试验（SHARP、4D、AURORA）证实：随着慢性肾脏病病情加重，他汀类药物的疗效逐步下降[21-23]。卡那单抗抗炎血栓结局研究（CANTOS）纳入近万名有心肌梗死病史、且残留炎症风险的患者，随机分为白介素 - 1β 单克隆抗体组与安慰剂组。该研究的亚组分析显示：对于估算肾小球滤过率＜60 mL/min/1.73m² 的患者，基线高敏C 反应蛋白、白介素 - 6 升高（而非低密度脂蛋白），是复发性主要不良心血管事件与全因死亡的危险因素[24]。 👩🎓 四、慢性肾脏病现有抗炎相关治疗手段 目前慢性肾脏病的主流治疗方案包括生活方式干预，以及血管紧张素转换酶抑制剂（ACEI）/ 血管紧张素受体拮抗剂（ARB）、强化血压管控、钠 - 葡萄糖协同转运蛋白 2（SGLT2）抑制剂、非甾体盐皮质激素受体拮抗剂，近年胰高血糖素样肽- 1（GLP-1）受体激动剂也被纳入标准治疗。上述药物是慢性肾脏病管理的核心用药，且部分药物兼具一定抗炎作用[25]。 肾素- 血管紧张素系统参与多种疾病的炎症反应，因此血管紧张素转换酶抑制剂 / 血管紧张素受体拮抗剂可发挥抗炎效果[26]；钠 - 葡萄糖协同转运蛋白 2 抑制剂主要通过作用于巨噬细胞，减轻机体低度慢性炎症[27]；胰高血糖素样肽 - 1 受体激动剂则可在全身多系统（包含肾脏）发挥抗炎作用[28]。但这类药物并非以靶向炎症通路为核心，因此直接靶向炎症通路成为全新研究方向，旨在降低慢性肾脏病患者的动脉粥样硬化性心血管疾病风险、延缓肾病进展。 👩🎓 五、靶向慢性肾脏病炎症的新型治疗药物 过去15 年中，靶向细胞因子的抗炎疗法逐步应用于慢性肾脏病相关研究。目前相关试验以早期探索性研究为主，针对临床终点的大型临床试验也已陆续启动。当前药物研发技术已可实现对各类目标细胞因子的阻断，药企也可快速研发靶向细胞因子、细胞因子受体及其他相关分子的新型抗炎药物。 促炎细胞因子与慢性肾脏病、终末期肾病（ESKD）患者的多项不良预后明确相关，且已有部分证据证实二者存在因果关系，这为细胞因子抗炎疗法应用于慢性肾脏病与维持性透析人群提供了充分理论依据[3]。但临床应用仍存在顾虑：晚期慢性肾脏病与终末期肾病患者处于免疫激活与免疫抑制并存的特殊状态，用药安全性需重点评估。下文结合临床试验，逐一介绍目前靶向慢性肾脏病、终末期肾病炎症的在研药物（见图2）。早期试验主要聚焦药物安全性、抗炎有效性及心血管风险改善，现阶段针对肾病进展终点的临床试验也已开展。各研究的试验设计与详细结果见表1。 图1 慢性肾脏病的炎症信号通路及潜在治疗靶点 先天免疫系统激活诱发的无菌性炎症，是慢性肾脏病及继发动脉粥样硬化、心血管疾病的核心驱动因素，该过程依赖NLRP3 炎症小体活化。目前多项正在开展的临床试验，药物靶点包括：NLRP3 炎症小体、白介素 - 1 / 白介素 - 1 受体、白介素 - 6 / 白介素 - 6 受体。 图2 慢性肾脏病炎症靶向治疗临床试验分期 按药物类别、候选药物划分，展示慢性肾脏病和/ 或维持性透析人群中，炎症靶向药物 已完成临床试验（浅蓝色标注）与正在开展临床试验（深蓝色标注） 的分期。  表1汇总：慢性肾脏病与终末期肾病中，以改善肾脏和 / 或心血管终点为目标的炎症靶向临床试验 👩🎓（一）白介素- 1 及白介素 - 1 受体抑制剂 2011 年，Hung等人开展了首个针对维持性血液透析患者的细胞因子抗炎临床试验[37]。该研究纳入 22 名合并全身炎症的透析患者，随机分为两组，分别使用白介素 - 1 受体拮抗剂阿那白滞素或安慰剂，干预时长4 周。结果显示：研究主要终点超敏 C 反应蛋白、次要终点白介素 - 6 水平均显著下降，且未发生严重不良事件。 后续Dember等人开展的试验纳入 80 名维持性血液透析患者，给予阿那白滞素或安慰剂干预 24 周[38]。结果显示患者白介素 - 6 水平下降，但超敏 C 反应蛋白降幅无统计学差异；分析认为，该现象与药物半衰期较短有关。 2017 年，研究者针对 42 名3~4 期慢性肾脏病、超敏 C 反应蛋白＞2 mg/L的患者开展生理学研究[29]，使用利纳西普干预12 周。结果显示：反映血管内皮功能的肱动脉血流介导的舒张功能提升 30%，超敏 C 反应蛋白下降 55%。联合分析阿那白滞素透析试验与利纳西普肾病试验的数据发现，抑制白介素- 1 通路还可改善高密度脂蛋白的抗炎、抗氧化能力[41]。 卡那单抗抗炎血栓结局研究（CANTOS）证实，直接靶向炎症可降低心血管不良事件风险[42,43]。该研究中 18.6% 的受试者估算肾小球滤过率＜60 mL/min/1.73m²，该亚组中位估算肾小球滤过率为 50（42~56）mL/min/1.73m²。与整体人群结果一致，卡那单抗可使该亚组患者主要不良心血管事件风险降低 18%[30]；但估算肾小球滤过率、尿白蛋白/ 肌酐比值及肾脏不良事件均未出现具有临床意义的改善。 整体试验及慢性肾脏病亚组中，卡那单抗组与安慰剂组的不良事件总发生率无明显差异，但致死性感染发生率出现小幅、具有统计学意义的升高（发生率：0.85 / 百人年 vs 0.36 / 百人年）。这一罕见但严重的安全隐患，可能限制卡那单抗及其他抗细胞因子药物在心血管风险防控中的临床应用。 此外研究发现，治疗后体内白介素- 18、白介素 - 6 水平仍偏高的患者，残余炎症风险（治疗后仍发生主要不良心血管事件的风险）也更高。这提示：同时阻断白介素- 1β 与白介素 - 18 信号通路的 NLRP3 炎症小体抑制剂，具备进一步研发价值[44]。 👩🎓（二）白介素- 6 及白介素 - 6 受体抑制剂 Ziltivekimab是靶向白介素 - 6 的人源单克隆抗体。其一期随机剂量递增试验纳入 3~4 期慢性肾脏病、合并慢性炎症（超敏 C 反应蛋白＞2 mg/dL）的患者，分为 3 个剂量组（5 mg、15 mg、50 mg），按 3:1 比例分配药物与安慰剂，单次皮下给药[31]。结果显示：15 mg、50 mg 剂量可将所有受试者的超敏 C 反应蛋白降至 2 mg/dL 以下，且未出现严重不良事件。 后续RESCUE 试验为双盲、随机、安慰剂对照 Ⅱ 期研究，纳入 3~5 期慢性肾脏病、基线超敏 C 反应蛋白≥2 mg/L 的患者，分别给予 7.5 mg、15 mg、30 mg Ziltivekimab（每 4 周皮下给药）或安慰剂，干预最长 24 周[32]。研究主要终点为干预 12 周时的超敏 C 反应蛋白水平，结果显示所有剂量组均可降低超敏C 反应蛋白，且全程未出现持续性3~4 级中性粒细胞减少、血小板减少。日本开展的 RESCUE-2 试验重复验证了上述结论[33]。 针对维持性血液透析人群的Ⅰ/Ⅱ 期研究显示，Ziltivekimab可降低超敏 C 反应蛋白等炎症标志物，同时减少促红细胞生成素的使用剂量[39]。白介素 - 6 可通过调控铁调素基因转录，直接干扰铁代谢[45]，这也解释了为何白介素 - 6 抑制剂可改善慢性肾脏病合并的炎症相关性贫血。 目前多项白介素- 6 抑制剂临床试验仍在推进： 1.TRANQUILITY 试验：Pacibekitug（TOUR006，抗白介素 - 6 单克隆抗体）的 Ⅱ 期研究，纳入 143 名 3~4 期慢性肾脏病、超敏 C 反应蛋白≥2 mg/mL 的成年患者，分不同剂量与给药频次干预 150 天，主要终点为超敏 C 反应蛋白变化，预计 2025 年 12 月完成； 2.ZEUS 试验：Ziltivekimab Ⅲ 期研究，纳入超 6200 名合并动脉粥样硬化、3~4 期慢性肾脏病、超敏 C 反应蛋白≥2 mg/dL 的成年患者，每月皮下给药 15 mg，最长干预 4 年，主要终点为主要不良心血管事件，肾脏复合终点为次要指标，预计 2026 年 6 月完成； 3.POSIBIL6ESKD 试验：Clazakizumab（抗白介素- 6 单克隆抗体）Ⅲ 期研究，目标入组 2310 名维持性透析、超敏 C 反应蛋白≥2 mg/L，且合并糖尿病或动脉粥样硬化性心血管疾病的患者，随访最长约 5 年，主要终点为心血管死亡或心肌梗死首次发生时间，预计 2029 年 8 月完成。 Clazakizumab的 2b 期试验纳入 127 名维持性血液透析、超敏 C 反应蛋白≥2 mg/L 的患者，分为 2.5 mg、5 mg、10 mg 剂量组（每 4 周透析期间静脉给药）与安慰剂组，干预至少 12 周，部分受试者延长至 24 周[40]。结果显示：各剂量组均可降低超敏 C 反应蛋白、纤维蛋白原、血清淀粉样蛋白 A、脂蛋白 (a) 等指标，血清白蛋白水平升高；全程无持续性 3~4 级血小板减少、中性粒细胞减少，但 10 mg 剂量组严重感染例数略高于对照组。 👩🎓（三）NLRP3 炎症小体抑制剂 抗白介素- 1 生物制剂无法阻断炎症小体介导的细胞死亡及白介素 - 18 信号传导，因此靶向NLRP3 炎症小体上游通路的药物具备独特研发潜力。 秋水仙碱是一种非特异性抗炎药物，临床常用于痛风治疗，价格远低于单克隆抗体。该药可抑制NLRP3 炎症小体活化，目前已获美国食品药品监督管理局批准，用于确诊动脉粥样硬化性心血管疾病患者的二级预防；COLCOT、LoDoCo2 两项临床试验也证实，秋水仙碱可降低慢性冠心病患者的心血管事件风险[46,47]。 现阶段肾病领域秋水仙碱相关临床试验： 1.REPAIR 试验（Ⅰ 期）：分为两组，分别纳入100 名非透析晚期慢性肾脏病（估算肾小球滤过率≤30 mL/min/1.73m²）患者、100 名维持性透析患者，开放标签给予 0.3 mg、0.6 mg 每日口服，干预 8 周，最长随访 17 周，主要评估药物耐受性与早期停药情况，预计 2026 年 5 月完成； 2.Ⅱ 期随机、安慰剂对照交叉试验：纳入估算肾小球滤过率15~75 mL/min/1.73m²、尿白蛋白 / 肌酐比值＞30 mg/g 的慢性肾脏病患者，每日口服 0.3 mg 秋水仙碱或安慰剂，每阶段干预 4 周，主要终点为左心室整体纵向应变，预计 2026 年 11 月完成。 注：晚期慢性肾脏病患者肾脏清除能力下降，使用秋水仙碱需严密监测，肌毒性风险会显著升高[3]。 AZD4144为直接靶向NLRP3 炎症小体的新型抑制剂，目前开展两项 Ⅰ 期试验： 1.1b 期试验：纳入28 名合并动脉粥样硬化性心血管疾病、3 期慢性肾脏病、超敏 C 反应蛋白＞2 mg/dL 的患者，单次口服给药，随访 4 周，评估不良事件、白介素 - 6、超敏 C 反应蛋白、白介素 - 18 及药效学指标，预计 2025 年 8 月完成； 2.Ⅰ 期试验：纳入非透析晚期慢性肾脏病（估算肾小球滤过率15~30 mL/min/1.73m²）、维持性终末期肾病患者及健康对照共 41 人，单次口服给药，院内观察 7 天，出院后再随访 7 天，主要评估药代动力学与治疗相关不良事件，该试验已于 2025 年 4 月完成，结果尚未正式发表。 👩🎓（四）其他抗炎治疗药物 核因子红细胞2 相关因子 2（Nrf2）激动剂 核因子红细胞2 相关因子 2 是兼具抗氧化、抗炎作用的转录因子，在慢性肾脏病患者体内表达下调[49]。Bardoxolone是该靶点代表药物： BEAMⅡ 期试验：纳入227 名合并 2 型糖尿病的慢性肾脏病患者，给予不同剂量Bardoxolone干预24 周，结果显示 24 周时估算肾小球滤过率明显改善，且疗效可维持至干预后 52 周[34]； BEACONⅢ 期试验：纳入 2185 名合并 2 型糖尿病的 4 期慢性肾脏病患者，因用药组心力衰竭风险升高、尿白蛋白排泄增加，试验被数据与安全监查委员会提前终止；最终证实该药无法降低终末期肾病、心血管死亡风险[35]。尽管现有试验结果不佳，但新型核因子红细胞2 相关因子 2 激动剂仍在持续研发中[50]。 衰老清除剂 衰老清除剂可诱导衰老细胞凋亡，是全新的抗炎方向。一项Ⅰ 期试验纳入 9 名合并 2 型糖尿病的 3b~4 期慢性肾脏病患者，联合使用达沙替尼+ 槲皮素口服治疗3 天[36]。结果显示：受试者脂肪组织内衰老细胞数量减少，白介素 - 1α、白介素 - 6、基质金属蛋白酶 9、基质金属蛋白酶 12 等衰老相关分泌表型因子水平同步下降。目前衰老清除剂在抗衰老及其他慢性病领域的试验不断增多，也有望成为慢性肾脏病治疗的新方向[51]。 其他新兴抗炎靶点 除上述药物外，JAK-STAT 抑制剂、免疫检查点调控、中性粒细胞胞外诱捕网形成抑制剂、趋化因子信号调控、巨噬细胞胞葬作用等，也是血管炎症领域的前沿研究方向[52]。 并非所有抗炎药物均能带来临床获益：心血管炎症降低试验（CIRT）显示，低剂量甲氨蝶呤无法降低合并 2 型糖尿病或代谢综合征的动脉粥样硬化性心血管疾病患者的心血管事件风险（甲氨蝶呤常用于类风湿关节炎等炎症性疾病）[53]。该结果也凸显了研发慢性肾脏病相关心血管疾病抗炎药物的难度。 👩🎓 六、临床试验与临床应用的挑战及考量（见图3）临床试验与科研层面挑战 1.多数患者无法达到试验入组标准（主要为超敏C 反应蛋白阈值要求）； 2.可纳入患者主观感受类终点指标（如乏力），提升受试者入组率； 3.慢性肾脏病（尤其透析人群）并发症多、中途退出率高，试验设计需提前应对； 4.部分研究中心因安全顾虑，不愿参与相关临床试验； 5.需进一步探索疾病机制，挖掘具备转化应用价值的全新药物靶点。 临床落地应用层面挑战 1.单克隆抗体类药物价格高昂，需完善医保及付费保障机制； 2.需保障不同人群均可公平获得药物治疗； 3.需权衡免疫功能受损风险与药物带来的心血管、肾脏获益； 4.精准筛选最佳适用人群与药物应答者； 5.明确药物最佳治疗时机与疗程。 图3 慢性肾脏病炎症靶向疗法：试验设计、科研探索及临床应用的挑战与考量 汇总了炎症靶向药物用于慢性肾脏病、终末期肾病治疗时，临床试验与科研工作、临床落地应用两大维度的现存问题与注意事项。 👩🎓 七、结论与未来展望 近十年间，靶向细胞因子的抗炎疗法在慢性肾脏病慢性全身性炎症的治疗领域取得了长足进展。目前已开展的短期、小样本试验未发现明显安全风险，但仍需等待长期、大样本、纳入肾脏终点指标的临床试验，进一步验证药物安全性。 该领域机遇与挑战并存，多项Ⅲ 期临床试验正在推进，学界也在积极攻克现存难题。我们期待后续试验结果公布，推动炎症靶向疗法真正应用于慢性肾脏病临床诊疗。 👩🎓 引用原文： Nowak K, Chonchol M. Targeting Inflammation in CKD. American Journal of Kidney Diseases, 2025; 86, 803-813

“Hopefully we can project that internal confidence externally and get some trust earned back,” Novo's CEO said in an interview with Fierce. In the air-conditioned haven of the Hilton just downriver from the American Diabetes Association’s 2026 Scientific Sessions in New Orleans, Mike Doustdar spoke with a quiet confidence and a smile as he acknowledged Novo Nordisk’s stumbles in recent years. Although the first three financial quarters of Doustdar's tenure have come with their share of obstacles, the unprecedented launch of Novo’s oral Wegovy offering in obesity this year added much-needed texture to a market where Eli Lilly had managed to assert its dominance with Zepbound. Meanwhile, Novo’s ethos of pitching Wegovy's ingredient semaglutide and the company's future chronic weight loss offerings as holistic metabolic treatments rather than drugs to shed pounds alone was borne out in a bevy of obesity readouts at the conference.Still, even with the humidity bearing down on patients, media and executives in the Crescent City this past weekend, Doustdar kept his cool as he reflected on the direction Novo is heading under his stewardship. “I have said publicly I am a lot more optimistic today than the day I got the job, on many fronts,” Doustdar said in an interview with Fierce, away from the bustle of the conference.“I was always positive about, of course, Novo Nordisk’s core capabilities [and] culture. I’ve been here for 34 years, and you have to like the company, otherwise, I guess you wouldn’t stay here so long,” he quipped. Doustdar, who assumed the role of Novo’s President and CEO from longtime leader Lars Fruergaard Jørgensen in August 2025, got his start at the Danish drug giant in 1992, beginning his professional journey in the unassuming post of an office clerk for the company in Vienna, Austria. By the summer of 2025, when Novo was in dire need of a sea change, Doustdar was overseeing the company's ex-U.S. operations. Despite the size of this role, Doustdar was relatively unknown outside of the Copenhagen-based company and the board’s decision to install him as CEO came as a shock to some industry soothsayers. Instead, they'd been putting their chips behind an external candidate, and likely one more intimately attuned to the U.S. commercial environment. Still, Doustdar—an Iranian-born, Austrian national—is no stranger to the U.S., having grown up in the country. Novo had explicitly tied Jørgensen’s departure to the tough competition it’s faced from chief rival Lilly in the U.S. and abroad. A plunge in the company’s share price had begun in mid-2024 as myriad factors, from branded competition from Zepbound to supply shortfalls and the rise of a GLP-1 compounding cottage industry, began to weigh on Novo’s fortunes. To Doustdar’s mind, Novo’s fundamentals were never in doubt. That said, “I did actually think that we need[ed] to become more competitive: That Novo has had many decades of competition, but in an environment that was moving slower,” the CEO told Fierce.Novo’s dedication in the fields of diabetes, obesity and metabolic health more broadly has remained consistent for many years, but the dynamics at play with the rise of the GLP-1 market for chronic weight management have turned the pressure up significantly. Novo traces its roots back more than 100 years to the Nordisk Insulinlaboratorium, which first commercialized production of insulin in Denmark in 1923 after the extraction and purification technique for the hormone was brought to the country from Canada. While insulin patients “often stay on those products for a very long period of time,” obesity is “a lot more like a fast consumer goods type of a behavior where they move, typically, on the next best thing, on the next cheapest thing—on the next buzzword out there,” Doustdar explained. “I was hoping that, of course, we can transform Novo Nordisk at its core, keeping some of the capabilities that we are very proud of, but building more skills and competencies that allow us to retain and sustain a durable leadership in this new obesity era,” Doustdar explained. “Nine months into it, I’m a lot more optimistic that we can.” That emboldened confidence in obesity is informed by strong execution in recent months across the areas of R&D, manufacturing and commercial execution, Doustdar argued. A bevy of late- and earlier-stage next-gen offerings for weight management and broader metabolic health were on display from Novo at ADA. And, after initial growing pains following Wegovy’s launch and a boom in overall GLP-1 popularity earlier in the decade, the pharma has long since resolved supply issues around its semaglutide products as it continues to make globe-trotting manufacturing expansions.In fact, the company's ability to ramp up production is now “second to none,” Doustdar argued. Meanwhile, on the proving ground of the U.S. weight loss market, “the most obvious proxy of that has been the launch of our Wegovy pill,” Doustdar said.Alongside multiple data readouts, Novo also used ADA to announce that the Wegovy pill, which officially launched in the U.S. on Jan. 5—several months ahead of Lilly’s rival GLP-1 pill Foundayo—has surpassed more than 3 million prescriptions, with the Danish company asserting that more than 80% of those scripts represent obesity patients new to the GLP-1 class. “In light of competition having arrived—if that’s not acceleration, I don’t know what is,” he told Fierce.  “Hopefully, we can project that internal confidence externally and get some trust earned back and continue with what we have started,” the CEO added. As for how Doustdar views his stewardship of the company in comparison to his predecessors, he acknowledged that he comes “from the commercial part of the organization.”“When you come from that part of the company, then you’re exposed much more to competition; that’s our job—to compete and sell,” he said. “So that’s one, I think, muscle memory I have.” At the same time, coming from the marketing battlefield, “you’re closer to the patients,” he pointed out. “You’re one step closer to the front line, and the interactions with the physicians, and seeing the burden of the disease and the suffering of patients more than when you are at the center,” he told Fierce. “Both of these things, I think, are crucial for this era of Novo Nordisk becoming more competitive and putting the patient at the center of what we do and asking ourselves how can we be a better company.” Doustdar has spoken previously of his perception that Novo suffered from the “curse of a leader” in both helping unlock the current obesity market and trial-running many of its hitherto unseen pitfalls. Now, in a further sign of the times, the CEO said “it’s interesting coming to ADA and recognizing how it’s more about obesity now than diabetes.”“In a humble way, our company takes pride in that, because when we went to this field, a lot of people were questioning us—and some maybe even made fun of us,” he said. “To see how all of that hard work and struggle led into pretty much all companies now having a booth talking about the same thing that excited you decades ago makes us very proud as a patient-centric organization, because the field of obesity is so large, unfortunately, that it requires many microphones, many people to echo the voice of these patients.”  The obesity époque In part, Doustdar tied some of Novo’s market struggles in recent years to an overemphasis on comparisons of raw weight loss statistics alone, whereas his company has long sought to treat obesity as a multifaceted condition marked by frequently intersecting comorbidities. As compared to Zepbound, Wegovy and its oral formulation both carry a key cardio risk reduction indication, which Novo has made essential to its pitch for the drug as going further than helping patients drop pounds alone. Lilly’s dual agonist, by contrast, holds a secondary indication in obstructive sleep apnea in the U.S. With Novo’s “beyond weight” messaging intact when it broke open the obesity market with Wegovy, Doustdar suggested that the company may have been “a little ahead of our time.” He suggested that Novo’s market capitalization and share price “suffered” in part “because the patients of that era ... were trying to tell us, ‘Well, we don’t want to go beyond weight; we want magnitude of weight loss.’”Recognizing the temperature, the company has attempted to adjust internally and “emphasize that it’s not only beyond weight—it’s weight and beyond,” Doustdar noted. “I don’t think we were wrong,” he stressed, again pointing to the mood and topics on display at this year’s conference.“This congress is again giving me hope,” the CEO explained. “For the first time, I’m hearing people not talk about a single digit number on weight loss effect, but a combination of things that a patient wants—better tolerability, maybe a pill instead of an injection, maybe the quality of the weight loss is the issue—all of those things that we started spending billions of dollars in, and maybe initially did not see the return, I think was the right thing.”  “The ‘trick,’” Doustdar added, “is not to get upset about it. To continue with confidence—listening to, of course, the market and adjusting where we fell—but also being confident that at the end of it, obesity does not kill. Conditions and complications related to obesity kill.” Faith in the plan is important, though it bears repeating that some of Novo’s key recent R&D endeavors have not been as successful as industry watchers, investors or the company may have hoped. Earlier this year, Novo’s CagriSema was dealt a major blow when results from an 809-participant open-label study pitting it against Lilly’s Zepbound ingredient tirzepatide showed Novo’s next-generation obesity candidate faring worse. CagriSema combines the novel amylin analog cagrilintide—which the company is also trialing on its own—with the company's approved GLP-1 receptor agonist semaglutide. At the 84-week mark, a 2.4/2.4-mg dose of CagriSema was linked to 23% average weight loss, while the 15-mg tizepatide dose used reached a weight loss figure of 25.5%. At the time, Novo’s chief scientific officer Martin Holst Lange, M.D., Ph.D., told journalists that Lilly's drug had “performed unusually well on efficacy compared to what has been typically seen in most previous trials of similar nature.” Novo submitted its U.S. application for CagriSema in obesity or overweight with at least one weight-related comorbid condition in December, with the FDA expected to weigh in on an approval later in 2026. Doustdar said his confidence in Novo’s overall pipeline is unshaken, arguing that the recent CagriSema readout is a good example of the world getting “obsessed with one number.” “We see this as a really good asset,” the CEO told Fierce. “And you can pick some numbers inside that maybe could be better, and some numbers that are best in class.” Combining the known profile and wealth of evidence on semaglutide with a newer approach like an amylin could offer “the best of the two worlds,” Doustdar suggested. “I think when the product comes out, people will be able to judge that this is a newer, better version of what already is a best-in-class product.” As Fierce's time with Doustdar drew to an end, the CEO made sure to overview other potential jewels embedded in the company's portfolio.“The rest of the pipeline is also incredibly exciting,” he said, pointing to multiple in-development assets like unimolecular peptide GLP-1 and amylin receptor agonist zenagamtide and its oral formulation. There's also cagrilintide, which Doustdar framed as a product with “a lower efficacy but better tolerability for those who choose to have less weight loss but also less nausea and vomiting.” Then there are a pair of triple agonists in the form of UBT251 and a second that targets amylin rather than glucagon in addition to GIP and GLP-1, plus more “specialized products” like Akero Therapeutics-developed fusion protein efruxifermin for fatty liver disease, the IL-6-targeting antibody ziltivekimab for cardiovascular conditions, and Novo’s potential next-generation insulins, including IcoSema. But those therapies are all later-stage, per Doustdar, who teased that Novo has more in store from its earlier pipeline that it plans to reveal at its upcoming capital markets day and throughout the rest of 2026. “We have seen a serious acceleration of our R&D organization and number of assets that are being developed,” he said.