检索问题
板块 3: CKM 0-4 分层下新型药物疗效、安全性的性别差异（临床转化重点） 按分层分类讨论新药，避免笼统描述，分层明确用药获益／不良反应性别区别，聚焦一线新药：SGLT2i、GLP-1RA、非奈利酮、新型他汀、ARNI CKM 0/1 层（早期高危、轻度损伤） GLP-1RA：女性减重、代谢改善获益更显著；男女心肾硬终点差异小；女性生殖道感染风 险更高。GLT2i：男女靶器官保护等效，但女性依从性更低。 CKM 2/3 层（中重度心肾损伤） 非奈利酮： 心肾保护作用男女一致；高钾血症风险无性别差异，男性偶见乳房发育。 ARNI：女性干咳、低血压不良反应发生率更高。 CKM 4 层（终末期） SGLT2i 降低心衰、肾病住院风险男女均获益；女性脱水、泌尿感染风险显著高于男性。 新药在 4 期女性人群临床试验入组不足，证据缺口大。 写作注意点 严格区分：疗效差异vs 不良反应／耐受性性别差异；标注荟萃分析、大型 RCT 分层亚组数据，标注交互 P 值； 指出现有研究缺陷：多数 RCT 未按 CKM 0-4 分层再做性别亚组分析。
以下是针对CKM（心血管-肾脏-代谢）疾病不同分层下，新型药物疗效和安全性的性别差异的详细讨论，重点关注一线新药：SGLT2i、GLP-1RA、非奈利酮和ARNI。
CKM 0/1 层（早期高危、轻度损伤）
在CKM 0/1层，患者通常处于早期高危或轻度损伤阶段，主要关注预防心血管和肾脏事件的发生。
GLP-1受体激动剂（GLP-1 RA）
- 疗效差异：
- 减重和代谢改善： 现有证据表明，GLP-1 RAs在多囊卵巢综合征（PCOS）女性肥胖患者中，能够显著降低体重指数（BMI）、腰围和血清甘油三酯水平 。PCOS是一种常见的内分泌疾病，其代谢紊乱与高雄激素血症密切相关，而高雄激素血症对脂肪、肝脏、胰腺、肌肉乃至大脑的代谢功能都有显著影响 。GLP-1 RAs还能降低PCOS女性的总睾酮水平 。这些发现提示GLP-1 RAs在女性中可能对减重和代谢改善具有更显著的获益。然而，目前缺乏直接比较GLP-1 RA在男性和女性CKM 0/1层患者中减重和代谢改善效果差异的荟萃分析或大型随机对照试验（RCT）亚组数据。
- 心肾硬终点： 总体而言，GLP-1 RAs与SGLT-2抑制剂均能降低全因死亡率、心血管死亡率、非致死性心肌梗死和肾衰竭的风险 。虽然GLP-1 RAs在降低非致死性卒中方面优于SGLT-2抑制剂 ，但目前没有高确定性证据表明在CKM 0/1层患者中，GLP-1 RAs对心肾硬终点的保护作用存在显著的性别差异。一项综合性网络荟萃分析显示，GLP-1 RAs能够降低全因死亡风险（OR 0.88，95% CI 0.82至0.93；高确定性），并降低心血管死亡、非致死性心肌梗死、心力衰竭住院和终末期肾病风险 。然而，这些研究并未专门针对CKM 0/1层患者进行性别分层分析。
- 不良反应/耐受性性别差异：
- 生殖道感染风险： SGLT-2抑制剂明确会导致生殖道感染（高确定性） 。GLP-1 RAs可能导致严重的胃肠道事件（低确定性） 。目前尚无确凿证据表明GLP-1 RAs在女性中导致生殖道感染的风险显著高于男性。虽然SGLT2i导致女性生殖道感染风险更高，但这并非GLP-1 RA的特有不良反应。
- 胆囊和胆道疾病： GLP-1 RA治疗与胆囊或胆道疾病风险增加相关（RR 1.37；95% CI 1.23-1.52），特别是胆石症（RR 1.27；95% CI 1.10-1.47）、胆囊炎（RR 1.36；95% CI 1.14-1.62）和胆道疾病（RR 1.55；95% CI 1.08-2.22） 。这种风险在用于减重的试验中更高（RR 2.29；95% CI 1.64-3.18），且与剂量和使用时长呈正相关 。目前研究未明确指出该不良反应在CKM 0/1层患者中存在性别差异。
- 胃肠道不良事件： GLP-1 RAs和替西帕肽（一种GIP/GLP-1受体双重激动剂）可能导致严重的胃肠道不良事件 。部分研究显示GLP-1 RAs在PCOS女性中可引起恶心和腹痛等轻微副作用 。然而，缺乏明确的证据表明在CKM 0/1层患者中，GLP-1 RAs引起的胃肠道不良事件在男女之间存在显著差异。
SGLT-2抑制剂（SGLT2i）
- 疗效差异：
- 靶器官保护： SGLT2i能够降低所有原因死亡率、心血管死亡率、非致死性心肌梗死和肾衰竭的风险（高确定性证据） 。一项大型荟萃分析显示，SGLT2i降低主要不良心血管事件（MACE）的风险（HR 0.91；95% CI 0.87-0.96），且在不同患者群体（包括高危动脉粥样硬化性心血管疾病糖尿病患者、心力衰竭患者或慢性肾病患者）中效果一致，并在所有关键亚组中均保持一致，包括是否存在动脉粥样硬化性心血管疾病、糖尿病、心力衰竭史、蛋白尿、慢性肾病分期以及风险组别 。这表明SGLT2i的靶器官保护作用在男女之间是等效的，但在CKM 0/1层的性别差异数据仍有限。SGLT2i还能降低心力衰竭住院的风险，且效果优于GLP-1 RAs 。
- 肾脏结局： SGLT2i降低慢性肾病（CKD）进展的风险（HR 0.62；95% CI 0.57-0.68），无论基线估算肾小球滤过率（eGFR）或白蛋白尿程度如何，包括在4期CKD患者或微量白蛋白尿患者中也有效 。这表明SGLT2i在肾脏保护方面具有广泛的适用性，但同样缺乏专门针对CKM 0/1层患者的性别亚组分析。
- 不良反应/耐受性性别差异：
- 女性依从性： 缺乏直接证据表明SGLT2i在CKM 0/1层女性中的依从性显著低于男性。然而，由于SGLT2i会导致生殖道感染（高确定性） ，这可能影响女性的用药依从性。研究表明，在肾移植受者中，SGLT2i（达格列净）普遍安全且耐受性良好，但未发现尿路感染或泌尿生殖道感染事件 。这可能表明在特定人群中，不良事件发生率有所不同。
- 脱水和泌尿感染风险： 针对CKM 4层患者的讨论中会更详细阐述SGLT2i导致女性脱水和泌尿感染风险显著高于男性的情况，这在CKM 0/1层患者中也需警惕，但程度可能较轻。
现有研究缺陷： 目前大多数大型RCT和荟萃分析并未专门按照CKM 0-4分层后再进行详细的性别亚组分析，尤其是在CKM 0/1层，这导致关于新药疗效和不良反应在男女之间是否存在显著差异的证据存在较大的缺口。
CKM 2/3 层（中重度心肾损伤）
在CKM 2/3层，患者通常存在中度至重度的心肾损伤，需要更积极的干预来延缓疾病进展并改善结局。
非奈利酮（Finerenone）
- 疗效差异：
- 心肾保护作用： 非奈利酮是一种选择性、非甾体盐皮质激素受体拮抗剂，在伴有2型糖尿病和慢性肾病的患者中，被证明可以改善心血管和肾脏复合结局 。
- 心血管结局： FIDELITY事后分析显示，非奈利酮对心血管事件（心血管死亡、非致死性心肌梗死、非致死性卒中或心力衰竭住院）的益处在不同年龄（P=0.42）和性别（P=0.99）类别中保持一致 。在FIGARO-DKD试验中，非奈利酮将主要心血管结局（心血管死亡、非致死性心肌梗死、非致死性卒中或心力衰竭住院）的风险降低了13%（HR 0.87；95% CI 0.76至0.98；P=0.03），主要归因于心力衰竭住院率的降低（HR 0.71；95% CI 0.56至0.90） 。FIDELIO-DKD试验也显示，非奈利酮降低了复合心血管结局的风险（HR 0.86；95% CI 0.75-0.99；P=0.034），且无论患者是否有动脉粥样硬化性心血管疾病史，治疗效果均无显著差异（交互P值=0.85） 。
- 心力衰竭住院： 非奈利酮降低心力衰竭住院风险的作用不受年龄影响（P=0.70），但在男性中似乎更显著（P=0.02） 。FIGARO-DKD的分析进一步证实，非奈利酮降低了新发心力衰竭（HR 0.68；95% CI 0.50-0.93；P=0.0162）和首次心力衰竭住院（HR 0.71；95% CI 0.56-0.90；P=0.0043）的风险，并且对心力衰竭结局的改善作用不受心力衰竭病史的影响 。
- 肾脏结局： 非奈利酮降低肾脏事件的作用在年龄小于65岁和65-74岁的组中观察到，但在≥75岁的组中不明显；然而，治疗效果的异质性不显著（P=0.51） 。在性别亚组中，非奈利酮持续降低肾脏事件的风险（P=0.85） 。此外，非奈利酮可降低蛋白尿并延缓eGFR下降，无论年龄和性别如何 。一项网络荟萃分析也指出，非甾体盐皮质激素受体拮抗剂（目前仅在慢性肾病患者中测试了非奈利酮）可能降低死亡率（0.89，0.79至1.00；中等确定性）和终末期肾病风险，并可能降低心血管死亡风险 。
- 新发房颤： FIDELIO-DKD研究显示，非奈利酮降低了新发房颤或房扑的风险（HR 0.71；95% CI 0.53-0.94；P=0.016） 。非奈利酮对主要肾脏复合结局和关键次要心血管结局的影响不受基线房颤病史的显著影响（交互P值分别为0.16和0.85） 。目前尚未有数据表明该作用存在性别差异。
- 心肾保护作用： 非奈利酮是一种选择性、非甾体盐皮质激素受体拮抗剂，在伴有2型糖尿病和慢性肾病的患者中，被证明可以改善心血管和肾脏复合结局 。
- 不良反应/耐受性性别差异：
- 高钾血症： 非奈利酮治疗组的高钾血症发生率高于安慰剂组，但停药率在所有亚组中均低于3% 。FIDELIO-DKD试验显示，非奈利酮组21.4%的患者和安慰剂组9.2%的患者经历了轻度高钾血症；非奈利酮组4.5%的患者和安慰剂组1.4%的患者经历了中度高钾血症 。高血清钾、低eGFR、尿白蛋白-肌酐比值升高、年龄较轻、女性、使用β受体阻滞剂是非奈利酮治疗组高钾血症的独立风险因素 。然而，该分析并未明确指出高钾血症的风险在不同性别的患者中存在显著差异。常规的钾监测和高钾血症管理策略可以最大限度地减少高钾血症的影响 。
- 乳房发育症： 在男性中，乳房发育症在不同年龄亚组中不常见，并且在非奈利酮和安慰剂治疗组之间发生率相同 。这表明非奈利酮引起的乳房发育症不具有性别特异性，且发生率较低。
- 总体安全性： 非奈利酮在不同年龄和性别亚组中表现出相似的安全性特征 。
血管紧张素受体脑啡肽酶抑制剂（ARNI）
- 疗效差异：
- 心力衰竭： 针对射血分数降低型心力衰竭（HFrEF）患者，沙库巴曲/缬沙坦（ARNI）与依那普利相比，在女性和男性中同样降低了心力衰竭住院、心血管原因死亡和全因死亡的风险 。PARADIGM-HF试验的事后分析显示，沙库巴曲/缬沙坦与依那普利相比，降低主要终点（心血管死亡或心力衰竭住院的复合事件）的风险在两性中程度相似：女性HR为0.76（95% CI 0.62-0.94），男性HR为0.80（95% CI 0.73-0.89）（交互P值=0.62） 。心力衰竭总住院率在女性中为0.66（95% CI 0.48-0.89），在男性中为0.80（95% CI 0.69-0.94）（交互P值=0.25） 。这表明ARNI在心力衰竭治疗中的疗效在男女之间是一致的。
- 肾脏结局： 一项针对高血压伴HFrEF老年患者的真实世界研究显示，ARNI治疗显著改善了LVEF和eGFR水平 。然而，该研究并未发现ARNI的疗效在性别之间存在差异 。
- 不良反应/耐受性性别差异：
- 干咳和低血压： PARADIGM-HF研究的分析表明，随机治疗中断和关注的不良事件在女性和男性中是相似的 。目前缺乏确凿证据表明ARNI在女性中导致干咳和低血压不良反应的发生率显著高于男性。相反，PARADIGM-HF研究的结果指出，沙库巴曲/缬沙坦是安全且耐受性良好的，无论性别如何 。
- 其他不良事件： 一项真实世界研究显示，在老年HFrEF患者中，ARNI治疗似乎有效且安全，未观察到与ARNI治疗相关的副作用 。
- 肾脏损伤： 尽管沙库巴曲/缬沙坦在治疗HFrEF患者中表现出肾脏保护作用，但也需关注可能对肾功能的影响。一项研究中观察到沙库巴曲/缬沙坦治疗组的eGFR得到显著改善 。
现有研究缺陷： 尽管针对非奈利酮和ARNI的大型RCT（如FIDELITY、FIGARO-DKD和PARADIGM-HF）包含了性别亚组分析，但这些分析通常是在整个研究人群中进行的，而非专门针对CKM 2/3分层内的性别差异。因此，在特定CKM分层下，这些药物疗效和不良反应的性别特异性差异仍需进一步细致研究。
CKM 4 层（终末期）
在CKM 4层，患者已进展到终末期心肾损伤，通常伴有显著的并发症，治疗目标主要是改善生活质量、降低住院和死亡风险。
SGLT-2抑制剂（SGLT2i）
- 疗效差异：
- 心衰、肾病住院风险： SGLT2i降低心力衰竭住院和肾病住院风险的益处在男女患者中均可获得 。一项针对SGLT2i的荟萃分析显示，SGLT2i降低CKD进展的风险（HR 0.62；95% CI 0.57-0.68），无论基线eGFR或白蛋白尿程度如何，包括在4期CKD患者（eGFR <30 mL/min/1.73 m2）中也有效（HR 0.71；95% CI 0.60-0.83；P for trend = .16） 。这表明SGLT2i在CKM 4层患者中对肾脏结局的保护作用是肯定的。SGLT2i也能显著降低心血管死亡（HR 0.86；95% CI 0.81-0.92）和心力衰竭死亡及突发性心脏死亡（HR 0.68和HR 0.86）的风险 。这些获益在不同亚组中基本一致，但目前缺乏直接针对CKM 4层患者的性别亚组分析，以明确心衰和肾病住院风险降低的性别差异。
- 不良反应/耐受性性别差异：
- 脱水和泌尿感染风险： 尽管具体的证据未直接指出SGLT2i在CKM 4层女性中脱水和泌尿感染风险显著高于男性，但SGLT2i普遍会导致泌尿生殖道感染（高确定性） 。女性由于生理结构原因，本身在用药时泌尿系统感染风险较高。因此，在终末期肾病患者中，其肾功能受损可能进一步增加此类风险，需特别关注女性患者的脱水和感染管理。在肾移植受者中，SGLT2i（达格列净）普遍安全且耐受性良好，且未观察到尿路感染或泌尿生殖道感染事件 。这可能提示在不同CKD分期或特定人群中，不良事件发生率存在差异。
新药在 4 期女性人群临床试验入组不足，证据缺口大
目前，针对CKM 4层（终末期）女性人群的新药临床试验入组普遍不足，导致在此分层下新药疗效和安全性的性别差异证据存在较大缺口。例如，一项针对SGLT2i的荟萃分析纳入了70,361名参与者，其中女性占35.0% 。FIDELITY事后分析中，男性占69.8% 。PARADIGM-HF研究中，女性占21.8% 。这些数据都显示女性患者在临床试验中的代表性不足，尤其是在晚期CKD患者中可能更为突出。这限制了对CKM 4层女性患者特异性获益和风险的评估。
现有研究缺陷：
- 缺乏细致分层下的性别亚组分析： 现有研究，包括许多大型荟萃分析和RCT的亚组分析，通常在整个研究人群中进行性别分析，而非针对CKM 0-4分层后再进行性别亚组分析。这使得我们难以准确评估不同CKM分层下新药疗效和不良反应的性别差异。
- 女性患者入组不足： 在许多针对心肾代谢疾病的临床试验中，女性患者的入组比例相对较低，特别是在疾病晚期阶段，这限制了对女性特定获益和风险的全面评估。
- 交互P值： 尽管一些研究报告了交互P值来评估治疗效果在不同性别之间是否存在显著差异，但这些数据往往是针对主要复合终点，而非所有次要结局或不良反应。对交互P值的解读需要谨慎，尤其是在样本量较小的亚组分析中。
新型他汀
关于新型他汀类药物在CKM 0-4分层下疗效和安全性的性别差异，在提供的证据中没有直接提及。他汀类药物主要用于降低血脂和预防动脉粥样硬化性心血管疾病。虽然他汀类药物在心血管疾病的预防和治疗中具有重要作用，但本次提供的文献主要聚焦于SGLT2i、GLP-1 RA、非奈利酮和ARNI等新型降糖和心肾保护药物，因此无法根据现有证据对新型他汀进行性别差异分析。
总结和临床转化重点
在CKM疾病管理中，新型药物如SGLT2i、GLP-1 RA、非奈利酮和ARNI展现出显著的心血管和肾脏保护作用。然而，其疗效和不良反应的性别差异在不同CKM分层下仍需更深入的探讨。
- CKM 0/1层：
- GLP-1 RA： 在女性中可能对减重和代谢改善（如降低总睾酮）有更显著的益处 。但心肾硬终点男女差异不明确。应警惕胆囊和胆道疾病风险，并密切监测胃肠道不良事件 。
- SGLT2i： 靶器官保护作用在男女之间可能等效，但需要关注女性患者的依从性问题，并警惕生殖道感染风险 。
- CKM 2/3层：
- 非奈利酮： 心肾保护作用在男女之间一致 。高钾血症风险管理是关键，但目前无明确证据表明风险存在性别差异 。男性乳房发育症不常见且发生率与安慰剂组相同 。
- ARNI： 在射血分数降低型心力衰竭患者中，心血管事件和心力衰竭住院的降低在男女之间相似 。目前缺乏证据表明女性干咳和低血压不良反应发生率更高，PARADIGM-HF研究显示其安全性在两性中是相似的 。
- CKM 4层：
- SGLT2i： 降低心力衰竭和肾病住院风险的益处在男女中均可见 。然而，需要特别关注女性脱水和泌尿感染风险，这可能因肾功能受损而加剧，导致女性患者的风险显著高于男性，但在提供的证据中没有直接明确的量化数据。
- 证据缺口： 新药在CKM 4层女性人群中的临床试验入组不足是当前研究的重大缺陷，导致在这一关键人群中，疗效和安全性性别差异的证据严重不足。
未来研究方向：
为了实现精准医疗，未来的临床试验应：
- 增加女性患者的代表性： 确保在各CKM分层中，女性患者有足够的入组比例，尤其是在晚期CKM患者中。
- 进行更细致的性别亚组分析： 不仅在整个研究人群中，更应在CKM 0-4各分层下进行详细的性别亚组分析，并报告疗效和不良反应的交互P值，以明确是否存在性别特异性差异。
- 关注女性特有的不良反应和依从性问题： 针对可能影响女性患者依从性或特有的不良反应进行专门评估和管理策略的开发。
通过这些努力，可以更好地指导临床实践，确保为不同性别和不同CKM分层患者提供最优化、个性化的治疗方案。
References
1Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.PubMed
Suetonia C Palmer, Britta Tendal, Reem A Mustafa, et al.
OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.
2Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials.PubMed
Liyun He, Jialu Wang, Fan Ping, et al.
IMPORTANCE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial. OBJECTIVE: To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations. DATA SOURCES: MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions. STUDY SELECTION: Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non-GLP-1 RA drugs in adults. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021. RESULTS: A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss. TRIAL REGISTRATION: PROSPERO Identifier: CRD42021271599.
3SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis.PubMed
Brendon L Neuen, Robert A Fletcher, Stefan D Anker, et al.
IMPORTANCE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce chronic kidney disease (CKD) progression in individuals with type 2 diabetes, CKD, or heart failure. However, their effects in those with stage 4 CKD or little to no albuminuria remain uncertain. OBJECTIVE: To assess whether estimated glomerular filtration rate (eGFR) or degree of albuminuria, measured by urinary albumin to creatinine ratio (UACR), modifies the effects of SGLT2 inhibitors on kidney outcomes. DATA SOURCES: SGLT2 inhibitor trials participating in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C). STUDY SELECTION: Randomized, double-blind, placebo-controlled trials within SMART-C evaluating an SGLT2 inhibitor with label indications for reducing CKD progression including at least 500 participants in each group with at least 6 months of follow-up. DATA EXTRACTION AND SYNTHESIS: Treatment effects in individual trials were pooled using inverse variance-weighted meta-analysis. MAIN OUTCOMES AND MEASURES: CKD progression, defined as kidney failure, at least 50% reduction in eGFR, or death due to kidney failure. Other outcomes included annual rate of eGFR decline and kidney failure. RESULTS: Among 70 361 participants (mean [SD] age, 64.8 [8.7] years; 24 595 [35.0%] females) in 10 randomized trials, 2314 (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57-0.68]), irrespective of baseline eGFR (HR of 0.61 [95% CI, 0.52-0.71] for eGFR ≥60 mL/min/1.73 m2; 0.57 [95% CI, 0.47-0.70] for eGFR of 45 to <60 mL/min/1.73 m2; 0.64 [95% CI, 0.54-0.75] for eGFR of 30 to <45 mL/min/1.73 m2; and 0.71 [95% CI, 0.60-0.83] for eGFR <30 mL/min/1.73 m2; P for trend = .16) and baseline albuminuria (HR of 0.58 [95% CI, 0.44-0.76] for albuminuria ≤30 mg/g; 0.74 [95% CI, 0.57-0.96] for >30-300 mg/g; and 0.57 [95% CI, 0.52-0.64] for more than 300 mg/g; P for trend = .49). Although the magnitude of protection varied, SGLT2 inhibitors reduced the annual rate of eGFR decline across all eGFR and UACR subgroups, including when participants with and without diabetes were analyzed separately. SGLT2 inhibitors also reduced the risk of kidney failure alone (HR, 0.66 [95% CI, 0.58-0.75]). CONCLUSIONS AND RELEVANCE: In this meta-analysis, SGLT2 inhibitors were found to lower the risk of CKD progression regardless of baseline eGFR or albuminuria, including in patients with stage 4 CKD or minimal albuminuria, supporting their routine use to improve kidney outcomes across the full spectrum of kidney function among patients with type 2 diabetes, CKD, or heart failure.
4Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials.PubMed
Shweta Bansal, Maria E F Canziani, Rita Birne, et al.
OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); P=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); P=0.99). Effects on HHF reduction were not modified by age (P=0.70) but appeared more pronounced in males (P=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (P=0.51). In sex subgroups, finerenone consistently reduced kidney events (P=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.
5Comprehensive Analysis of the Effects of Sacubitril/Valsartan According to Sex Among Patients With Heart Failure and Reduced Ejection Fraction in PARADIGM-HF.PubMed
Misato Chimura, Jawad H Butt, Shingo Matsumoto, et al.
BACKGROUND: Women with heart failure (HF) ejection fraction appeared to respond more favorably to sacubitril/valsartan, compared with valsartan, than men in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), driven by a greater reduction in total (first and recurrent) HF hospitalizations. Sex-specific efficacy and safety of sacubitril/valsartan in PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) remain unreported. METHODS AND RESULTS: This post hoc analysis of PARADIGM-HF examined sex-based outcomes in patients with HF and reduced ejection fraction randomized to sacubitril/valsartan or enalapril. The primary end point was a composite of cardiovascular death or HF hospitalization. Secondary and exploratory efficacy outcomes, biomarker changes, and safety outcomes were also assessed. Among 8399 participants, 1832 (21.8%) were women. Women were older, had worse New York Heart Association functional class and Kansas City Cardiomyopathy Questionnaire scores, more symptoms of HF, and lower estimated glomerular filtration rate, yet had lower rates of HF hospitalization (and other worsening of HF) and cardiovascular death than men. Compared with enalapril, sacubitril/valsartan reduced the risk of the primary end point to a similar extent in both sexes: hazard ratios, 0.76 (95% CI, 0.62-0.94) in women and 0.80 (95% CI, 0.73-0.89) in men (-interaction=0.62). Results were consistent for the individual components of the primary outcome. The rate ratio for total HF hospitalizations was 0.66 (95% CI, 0.48-0.89) in women and 0.80 (95% CI, 0.69-0.94) in men (-interaction=0.25). Randomized treatment discontinuation and adverse effects of interest were similar in women and men. CONCLUSIONS: In PARADIGM-HF, sacubitril/valsartan, compared with enalapril, reduced the risk of HF hospitalizations, death from cardiovascular causes, and death from any cause similarly in women and men with HF with reduced ejection fraction. In addition, sacubitril/valsartan was safe and well tolerated, irrespective of sex. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.
6Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.PubMed
Qingyang Shi, Kailei Nong, Per Olav Vandvik, et al.
OBJECTIVE: To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Ovid Medline, Embase, and Cochrane Central up to 14 October 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach. RESULTS: The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes). CONCLUSIONS: This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022325948.
7Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies.PubMed
Miguel A Sanchez-Garrido, Manuel Tena-Sempere
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited. SCOPE OF REVIEW: This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions. MAJOR CONCLUSIONS: Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
8Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.PubMed
Siddharth M Patel, Yu Mi Kang, KyungAh Im, et al.
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], <0.0001) with a consistent effect across all 3 patient populations (=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], <0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], =0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], =0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.
9Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.PubMed
Bertram Pitt, Gerasimos Filippatos, Rajiv Agarwal, et al.
BACKGROUND: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. METHODS: In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events. RESULTS: A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). CONCLUSIONS: Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).
10The role of sacubitril/valsartan in the treatment of chronic heart failure with reduced ejection fraction in hypertensive patients with comorbidities: From clinical trials to real-world settings.PubMed
Alberto Mazza, Danyelle M Townsend, Gioia Torin, et al.
BACKGROUND: Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities. METHODS: In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 % male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected. RESULTS: NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting from class III to II, and 55.4 vs. 25.2 %, from class II to I, p < 0.05 for all). A significant improvement in LVEF and eGFR levels was found in the ARNI arm compared to controls (42.4 vs. 34.2 %, 73.8 vs. 61.2 mL/min, respectively; p < 0.001 for all). NT-proBNP, clinic systolic and diastolic BP, blood glucose, HbA1c and UA values were reduced in both treatment arms, but they were lower in the ARNI arm compared controls (3107 vs. 4552 pg/mL, 112.2 vs. 120.4 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9 vs. 6.4 mg/dL, respectively, p < 0.05). Mortality and re-hospitalization for HF was lower in the ARNI arm than controls (20.1 vs. 33.6 % and 27.7 vs. 46.3 % respectively; p < 0.05 for all). Gender differences were not found in either arm. No patients refused to continue the study, and no side effects to the ARNI treatment were observed. CONCLUSIONS: In elderly patients with HFrEF and comorbidities, ARNI treatment seems effective and safe. The improvement in LVEF and cardiac remodeling, BP, eGFR, serum glucose, UA and HbA1c could be the mechanisms by which ARNIs play their beneficial role on clinical outcomes. However, these results need to be confirmed in studies involving a greater number of subjects, and with a longer follow-up.
11Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria.PubMed
Brendon L Neuen, Hiddo J L Heerspink, Priya Vart, et al.
BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. METHODS: We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney, and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. RESULTS: Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% CI, 0.55-0.76) for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI, 3.0-5.7), with a number needed to treat of 23 (95% CI, 18-33). For a 50-year-old patient commencing combination therapy, estimated major adverse cardiovascular event-free survival was 21.1 years compared with 17.9 years for conventional care (3.2 years gained [95% CI, 2.1-4.3]). There were also projected gains in survival free from hospitalized heart failure (3.2 years [95% CI, 2.4-4.0]), chronic kidney disease progression (5.5 years [95% CI, 4.0-6.7]), cardiovascular death (2.2 years [95% CI, 1.2-3.0]), and all-cause death (2.4 years [95% CI, 1.4-3.4]). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for major adverse cardiovascular events (2.4 years [95% CI, 1.1-3.5]), chronic kidney disease progression (4.5 years [95% CI, 2.8-5.9]), and all-cause death (1.8 years [95% CI, 0.7-2.8]). CONCLUSIONS: In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.
12The efficacy and safety of GLP-1 agonists in PCOS women living with obesity in promoting weight loss and hormonal regulation: A meta-analysis of randomized controlled trials.PubMed
Beatriz Austregésilo de Athayde De Hollanda Morais, Vitória Martins Prizão, Mariana de Moura de Souza, et al.
BACKGROUND: The efficacy of GLP1 receptor agonists (GLP1-RAs) in treating polycystic ovarian syndrome (PCOS) remains unclear. While GLP1-RAs are known to promote weight loss in patients with diabetes and living with obesity, their impact on weight reduction and hormonal regulation in women with PCOS is understudied. Therefore, we aimed to assess the efficacy of GLP1-RAs in PCOS women living with obesity through a meta-analysis, comparing their effects to placebo. HYPOTHESIS: The use of GLP1-RAs in PCOS women living with obesity can reduce body mass index and waist circumference as well as improve hyperinsulinism, and hyperandrogenism as well as normalize total testosterone, total cholesterol and HOMA-IR markers in PCOS women living with obesity. METHODS: We systematically searched the PubMed, Cochrane Central, Scopus and Embase databases to identify randomized controlled trials (RCT) comparing GLP1-RAs versus placebo among women diagnosed with PCOS based on the Rotterdam Criteria. Our primary outcomes of interest included body mass index (BMI), triglycerides, waist circumference, total testosterone, total cholesterol, and HOMA-IR. We performed data extraction and quality assessment for studies that met the inclusion criteria. We pooled mean difference (MD) and 95 % confidence intervals (CI) with a random-effect model for continuous endpoints. RESULTS: We included 176 participants from four RCTs. Semaglutide and Liraglutide were used in 23 (13 %) and 103 (58 %) participants, respectively. GLP1-RAs use was associated with a significant reduction in waist circumference (MD: -5.16 cm; 95 % CI: -6.11 to -4.21; p ˂ 0.00001), body mass index (BMI) (MD: -2.42; 95 % CI: -3.10 to -1.74; p ˂ 0.00001), serum triglycerides (MD: -0.20; 95 % CI: -0.30 to -0.11; p ˂ 0.00001) and total testosterone levels (MD: -1.33; 95 % CI: -2.55 to -0.12; p = 0.03) when compared to placebo. There was no significant difference in total cholesterol (MD: -0.04; 95 % CI: -0.10 to 0.01; p = 0.15) and HOMA-IR (MD: -0.30; 95 % CI: -0.92 to 0.32; p = 0.35) levels. Adverse events information was available for 112 patients, where 49 had light side effects such as nausea and abdominal pain. CONCLUSION: The use of GLP1-RAs demonstrates efficacy in reducing BMI, triglycerides, waist circumference and total testosterone. There was no significant difference in total cholesterol and HOMA-IR levels. These results signify its viability as a favourable treatment option for managing PCOS symptoms in women living with obesity.
13Efficacy, Mechanisms, and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Kidney Transplant Recipients: A Randomized, Double-Blind, Placebo-Controlled Trial.PubMed
Vikas S Sridhar, Luxcia Kugathasan, Yuliya Lytvyn, et al.
KEY POINTS: The effIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients trial assessed the physiologic effects of sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients. In kidney transplant recipients, sodium-glucose cotransporter-2 inhibitors lowered mean arterial pressure after 1 week, reduced GFR, increased glucosuria, and were safe. Dapagliflozin was well tolerated in kidney transplant recipients, showing similar cardio-kidney effects seen in other groups; outcome trials in kidney transplant recipients are now needed. BACKGROUND: Cardiovascular and kidney protective mechanisms with 12 weeks of sodium-glucose cotransporter-2 inhibitor treatment (dapagliflozin 10 mg daily) were assessed in kidney transplant recipients (KTR) with and without type 2 diabetes. METHODS: This randomized double-blind, parallel-group, placebo-controlled study enrolled 52 KTR and comprised three sequential physiologic assessments under clamped euglycemia (4-6 mmol/L): baseline, at 1, and 12 weeks of treatment. The primary objective was to evaluate BP lowering with dapagliflozin. Secondary outcomes were iohexol-measured GFR, natriuresis, body composition, noninvasive cardiac output monitoring, arterial stiffness, heart rate variability, neurohormones, and safety. RESULTS: Fifty-one KTR completed the study-mean age 53±13 years, 62% with hypertension, 57% with type 2 diabetes, 50% on renin-angiotensin-aldosterone system inhibitors, and mean eGFR 68.2±24.4 ml/min per 1.73 m 2 . Compared with placebo, dapagliflozin did not lower systolic BP at 1 or 12 weeks, although it did reduce mean arterial pressure after 1 week (3.9 mm Hg; 95% confidence interval [CI], -7.5 to -0.2). Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to 1 week (4.2 ml/min per 1.73 m 2 ; 95% CI, -7.14 to -1.24 ml/min per 1.73 m 2 ) and 12 weeks (-3.49 ml/min per 1.73 m 2 ; 95% CI, -6.33 to -0.64). Dapagliflozin significantly increased glucosuria without altering proximal sodium handling or evidence of sympathetic activation. Acute decreases in arterial stiffness (carotid augmentation index, -3.5%; 95% CI, -6.0 to -1.1) were observed in the dapagliflozin group after 12 weeks, although this was not significant compared with placebo. Dapagliflozin was generally safe and well tolerated. No episodes of urinary tract or genitourinary infections were observed in either treatment group throughout the trial. CONCLUSIONS: Dapagliflozin activated expected physiologic pathways, although key differences observed in KTR might suggest mechanistic heterogeneity compared with nontransplant populations. Clinical trials evaluating sodium-glucose cotransporter-2 inhibitors in KTR are important to determine whether these mechanistic effects translate to improvements in kidney and cardiovascular outcomes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT04965935 . PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_02_09_KTS_February2026.mp3.
14Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial.PubMed
Rajiv Agarwal, Amer Joseph, Stefan D Anker, et al.
BACKGROUND: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo in FIDELIO-DKD. METHODS: This safety analysis defined hyperkalemia as ≥mild or ≥moderate based on serum potassium concentrations of >5.5 or >6.0 mmol/L, respectively, assessed at all regular visits. Cumulative incidences of hyperkalemia were based on the Aalen-Johansen estimator using death as competing risk. A multivariate Cox proportional hazards model identified significant independent predictors of hyperkalemia. Restricted cubic splines assessed relationships between short-term post-baseline changes in serum potassium or eGFR and subsequent hyperkalemia risk. During the study, serum potassium levels guided drug dosing. Patients in either group who experienced ≥mild hyperkalemia had the study drug withheld until serum potassium was ≤5.0 mmol/L; then the drug was restarted at the 10 mg daily dose. Placebo-treated patients underwent sham treatment interruption and downtitration. RESULTS: Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex, -blocker use, and finerenone assignment. Diuretic or sodium-glucose cotransporter-2 inhibitor use reduced risk. In both groups, short-term increases in serum potassium and decreases in eGFR were associated with subsequent hyperkalemia. At month 4, the magnitude of increased hyperkalemia risk for any change from baseline was smaller with finerenone than with placebo. CONCLUSIONS: Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.
15Sodium Glucose Cotransporter 2 Inhibitors Across the Spectrum of Cardiovascular Kidney Metabolic Syndrome.PubMed
Kevin Bryan Lo, Karim Iskarous, Rajiv Sankaranarayanan
The burden of metabolic diseases including diabetes and obesity is rising. Excess and dysfunctional adipose tissue can lead to inflammation and contribute to insulin resistance. Eventually, downstream effects include both cardiac and kidney disease across a spectrum of related risk factors and processes collectively known as the cardiovascular kidney metabolic (CKM) syndrome. Sodium glucose cotransporter 2 inhibitors (SGLT2i) by virtue of their action and robust clinical data play a central role in patients across the spectrum of CKM. The article summarizes the mechanisms and clinical evidence behind the benefits of SGLT2i across the spectrum of patients with CKM syndrome.
16Finerenone Reduces Risk of Incident Heart Failure in Patients With Chronic Kidney Disease and Type 2 Diabetes: Analyses From the FIGARO-DKD Trial.PubMed
Gerasimos Filippatos, Stefan D Anker, Rajiv Agarwal, et al.
BACKGROUND: Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes. METHODS: Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). RESULTS: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50-0.93]; =0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70-0.95]; =0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56-0.90]; =0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. CONCLUSIONS: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02545049.
17Rethinking the Diabetes-Cardiovascular Disease Continuum: Toward Integrated Care.PubMed
Alfredo Caturano, Cassandra Morciano, Katarzyna Zielińska, et al.
Type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD) are not merely coexisting epidemics but co-evolving manifestations of a shared cardiometabolic continuum. Despite advances in glycemic, lipid, and blood pressure control, residual cardiovascular risk remains high, underscoring the limitations of siloed approaches. In this perspective, we argue for reframing T2D and CVD as interconnected conditions driven by inflammation, adipose tissue dysfunction, and organ crosstalk. Beyond metformin, which remains foundational, several glucose-lowering drug classes are now evaluated not only for glycemic control but also for their cardiovascular and renal impact. Landmark trials and recent meta-analyses confirm that sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists improve cardiorenal outcomes. More recently, tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, has shown unprecedented efficacy in weight and glucose management, with potential to further transform cardiometabolic risk reduction. Yet enthusiasm for these therapies must be tempered by heterogeneity of response, treatment costs, and inequitable access. Integrated care models, supported by multidisciplinary teams, digital health tools, and value-based reimbursement, are essential to close the gap between trial efficacy and real-world outcomes. Attention to sex, age, ethnicity, and comorbidity profiles is critical to ensure equity, as is the adaptation of strategies to low- and middle-income countries where the burden of cardiometabolic disease is rapidly rising. Ultimately, advancing cardiometabolic medicine requires not only novel therapies but also a unifying framework that integrates biology, behavior, economics, and health systems to deliver the right treatment to the right patient at the right time.
18Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes.PubMed
Gerasimos Filippatos, Stefan D Anker, Rajiv Agarwal, et al.
BACKGROUND: The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. We report the effect of finerenone on individual cardiovascular outcomes and in patients with and without history of atherosclerotic cardiovascular disease (CVD). METHODS: This randomized, double-blind, placebo-controlled trial included patients with type 2 diabetes and urine albumin-to-creatinine ratio 30 to 5000 mg/g and an estimated glomerular filtration rate ≥25 to <75 mL per min per 1.73 m, treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite cardiovascular outcome included time to cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified cardiovascular analyses included analyses of the components of this composite and outcomes according to CVD history at baseline. RESULTS: Between September 2015 and June 2018, 13 911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 [95% CI, 0.75-0.99]; =0.034), with no significant interaction between patients with and without CVD (hazard ratio, 0.85 [95% CI, 0.71-1.01] in patients with a history of CVD; hazard ratio, 0.86 [95% CI, 0.68-1.08] in patients without a history of CVD; value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone versus 0.8% with placebo in patients with CVD and 2.2% with finerenone versus 1.0% with placebo in patients without CVD). CONCLUSIONS: Among patients with chronic kidney disease and type 2 diabetes, finerenone reduced incidence of the composite cardiovascular outcome, with no evidence of differences in treatment effect based on preexisting CVD status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02540993.
19CVOT Summit Report 2025: advances along the cardiovascular-kidney-metabolic disease continuum.PubMed
Oliver Schnell, Arnav Agarwal, Michel Azizi, et al.
The 11th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 20-21, 2025. The Summit provided a multidisciplinary forum to review and discuss recent outcome trials investigating emerging pharmacological therapies targeting diseases of the cardiovascular-kidney-metabolic (CKM) continuum. This report highlights the unique developments of 2025 discussed during the Summit, including the first head-to-head CVOT (SURPASS-CVOT), the growing evidence base for combination therapies across the disease spectrum, new insights into the inflammatory component of the CKM syndrome, and relevant policy developments. The first part of this report summarizes pioneering clinical trials addressing combination therapy with finerenone and empagliflozin (CONFIDENCE), the oral glucagon-like peptide-1 (GLP-1) receptor agonists orforglipron (ATTAIN-1), and the aldosterone synthase inhibitor (ASI) baxdrostat (BaxHTN). The second part presents recent guideline and policy developments discussed by experts in endocrinology, diabetology, cardiology, nephrology, hepatology, and general practice. In addition, advances in medical technology, particularly in continuous glucose and ketone monitoring, are highlighted, as well as emerging therapies for diseases of the CKM continuum. These include pharmacological agents for a broad spectrum of metabolic disorders such as metabolic liver disease and type 1 Diabetes (T1D) alongside emphasis on the importance of early detection and innovative treatment strategies. The 12th Cardiovascular Outcome Trial Summit will be held virtually on 19-20 November 2026 ( http://www.cvot.org ).
20Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes.PubMed
Gerasimos Filippatos, George L Bakris, Bertram Pitt, et al.
BACKGROUND: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models. OBJECTIVES: This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study. METHODS: Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m and received optimized doses of renin-angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF. RESULTS: Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53-0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively). CONCLUSIONS: In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. (EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993).