编者按：在第62届欧洲肾脏协会年会（ERA 2025）上，来自美国华盛顿大学的Katherine R. Tuttle教授接受了肾医线专访，围绕糖尿病肾病（DKD）治疗的前沿进展展开深度探讨，分享了其关于醛固酮合酶抑制剂、GLP-1 受体激动剂（如司美格鲁肽）等新兴治疗策略的最新进展，并就DKD多靶点联合治疗、治疗优先级排序、未来研究重点等话题提出了前瞻性见解。

醛固酮合酶抑制剂联合治疗：开启肾脏保护新维度

Tuttle教授研究团队关于Vicadrostat联合恩格列净的研究显示，该方案在 KDIGO 所有风险分层患者中均显著降低蛋白尿。她指出，这是一个令人振奋的治疗新方向。与传统的盐皮质激素受体拮抗剂不同，醛固酮合成酶抑制剂通过阻断醛固酮生成（而非受体）实现更彻底的醛固酮通路抑制。联合恩格列净后，我们不仅观察到更强的蛋白尿降低效果（这在Ⅱ期试验中预示临床获益），还发现血钾升高风险更小——这至关重要，因为高钾血症正是当前醛固酮阻断疗法的主要安全隐患。目前这一组合方案正在EASi-KIDNEY大型临床试验中验证：所有受试者均接受恩格列净，随后随机加用Vicadrostat或安慰剂。我们正迈向这种与SGLT2抑制剂联合治疗的新阶段。

Nephrology On-line: Your study on Vicadrostat combined with empagliflozin showed albuminuria reduction across KDIGO risk categories. What does this suggest about the potential role of aldosterone synthase inhibitors in the broader management of diabetic kidney disease?

Dr Tuttle: This is an exciting area for therapeutic development. The aldosterone synthase inhibitor class is designed to inhibit production of aldosterone as a way to block its injurious pathways in the kidney, as opposed to blocking at the receptor, like we do with mineralocorticoid antagonism, so we may get more complete aldosterone blockade. Combined with empagliflozin, we also see that there is a signal for greater efficacy. There is greater albuminuria-lowering, which is our readout in a phase II trial, that is likely to be clinically beneficial. But in addition, there is also a signal for less elevation in potassium. That is important because it could mitigate a major safety concern with blocking aldosterone, which is hyperkalemia. So, this is a very exciting new area, and it is being tested in a large-scale clinical trial called EASi-KIDNEY, where all the study participants get empagliflozin, and then they are randomized to either receive the vicadrostat or placebo. We are really moving on to testing this as a combination therapy with SGLT2 inhibition.

司美格鲁肽的独特优势：代谢与肾脏保护的 “全能选手”

Tuttle教授认为我们正经历CKD治疗的"文艺复兴"时期，无论是合并糖尿病还是不合并糖尿病的患者，都迎来了奇妙的机遇——SGLT2抑制剂、醛固酮拮抗剂、GLP-1受体激动剂相继涌现，叠加传统ACEI和RAS抑制剂，形成了丰富的治疗选择。她指出，现有研究尚未直接对比不同药物的肾脏获益，从总体获益来看，在减少肾功能丧失、预防肾衰竭、降低心血管事件和死亡风险方面，大多数这类药物的风险降低效果相当。而司美格鲁肽除了在肾脏保护方面具有相当的益处，其优势还在于其卓越的代谢改善能力：即便在eGFR降至15 ml/（min·1.73m2）的晚期肾病患者，甚至在透析和肾移植患者中，仍能有效降糖; 同时其对合并肥胖的CKD患者具有显著体重管理作用——这是其他药物不具备的特性。可以说，司美格鲁肽提供了“全方位获益”：既降低肾脏风险，又带来代谢益处，还能减少心血管风险。因此，Tuttle教授认为它是唯一能为2型糖尿病合并CKD患者提供其所需的全面降低风险策略的药物。

Nephrology On-line: The FLOW trial has generated significant attention regarding semaglutide’s impact on CKD progression. From your perspective, what makes semaglutide stand out compared to other current treatment options for patients with type 2 diabetes and CKD?

Dr Tuttle: I think that we are in a renaissance of new therapies for chronic kidney disease, including people with and without diabetes. It is a marvelous time. And it's wonderful that we now have a portfolio of new agents. We have SGLT2 inhibitors. We have aldosterone blockers, as we've talked about. And now we have GLP-1s. All this on top of conventional ACEs and ARBs. So, it is a fantastic time. We welcome all of these therapies. But if I had to say what would distinguish semaglutide, I would say that it has comparable benefits on kidney protection. Now, I have to qualify that statement because we haven't done a head-to-head comparison, but when we look at overall benefits on reducing loss of kidney function and preventing kidney failure, reducing cardiovascular events and deaths, most of these agents line up to be fairly comparable in terms of risk reduction. But I think what semaglutide would add is that it has potent metabolic effects that other drugs don't have. It is very effective at glucose lowering to GFRs as low as 15, even in dialysis and transplant. It is also very effective at weight management in people living with obesity who have CKD, which the other agents don't have. And then the cardiovascular benefits are really quite substantial. Again, I don't think we can compare them between agents, but what I would say is that we get the whole package. We get reduced kidney risk, we get metabolic benefits, and we get cardiovascular risk reduction. So, I think it is the only agent that provides the full portfolio of risk-reducing strategies that people with type 2 diabetes and CKD need.

多靶点联合治疗：现阶段如何优先排序？

面对SGLT2抑制剂、非甾体MRA、GLP-1受体激动剂、醛固醇合成酶抑制剂等多种可选药物，如何在不同风险人群中合理排序和组合治疗？Tuttle教授坦言，目前尚缺乏明确的循证顺序或联合用药方案，多基于现有小规模研究和临床经验。

她分享到，在CONFIDENCE研究中，非甾体MRA非奈利酮（一种与醛固酮合成酶抑制剂不同的有效醛固酮阻断策略）与SGLT2抑制剂同步起始显示了协同降低蛋白尿的效果。而她自己的醛固酮合成酶抑制剂研究则采用了先给予SGLT2抑制剂（恩格列净治疗8周，为导入期）、再加用醛固酮合成酶抑制剂的设计。因此，对于起始顺序，目前并无定论。

Tuttle教授建议：“在缺乏明确指南前，临床医生应对患者详细检查，根据患者的个体化风险进行优先级选择。例如，对于肥胖且2型糖尿病控制不佳的患者，可优先考虑GLP-1受体激动剂；而对于顽固性高血压患者，则可首先选择醛固酮通路阻断剂。”在获得关于联合治疗和用药顺序的数据（这些数据最终会有的）之前，关键在于根据患者的主要风险与未满足的治疗需求，量身定制治疗策略。

Nephrology On-line: With multiple therapeutic classes now available for DKD—such as SGLT2 inhibitors, MRAs, GLP-1RAs, and new agents like Vicadrostat—how should clinicians prioritize or sequence these therapies for different risk groups?

Dr Tuttle: Another great question, and I have to answer this in an opinion-based way because we haven't done the studies where we added therapies or tested different sequences. But that said, everything we are seeing is a signal to more kidney protection with combination therapy. Here at the meeting, we heard about the CONFIDENCE trial with very nice results of starting finerenone, which is an aldosterone blocker as a non-steroidal mineralocorticoid antagonist distinct from the aldosterone synthase inhibitors (ASi), but another effective strategy for aldosterone blockade, along with SGLT2s, showing additive benefits at least on albuminuria lowering. So, we will be using agents together. In that study, they gave both at the same time. In our aldosterone synthase inhibitor study, we had an eight-week run-in period where we gave empagliflozin for eight weeks, and then we added ASi. So which drug first? Whether we can start them at the same time or we have to wait, these are unknowns. But what can the clinician do now? I would say when all else fails, examine the patient, right? Look at the patient in front of you and say, what are the major risks this person faces? For a person living with obesity and type 2 diabetes that is inadequately controlled, maybe we would use a GLP-1 first because we need that metabolic benefit. On another person who perhaps has resistant hypertension, we might go for an aldosterone blocker ahead of another agent. Before we have the data, which will eventually come on combination therapies and sequencing, I think we have to make clinical decisions as best we can. The good news is we now have a portfolio of therapies, so you can look at your patient and say, what is the greatest risk and unmet need, and prioritize those drugs first. So that's the best answer I can give you today.

临床实践的下一个战场：落实、筛查与长期管理

展望未来，Tuttle教授认为当前糖尿病肾病治疗的核心问题已从“药物短缺”转变为“如何有效落实”。

令人担忧的是，尽管我们拥有如此多的高效治疗手段，真实世界的数据集却显示，即使是在我们有明确证据的在糖尿病合并CKD人群中，传统的ACEI/ARB的使用率也通常只有50%甚至更低。对电子病历的数据分析让我们意识到，我们的工作成效并非想象中那么好，这不仅体现在治疗方面，还体现在对疾病的认识和检测上，例如，糖尿病患者每年进行尿白蛋白筛查的比例不足50%甚至低至10%。

我们必须首先诊断出疾病，然后至少要开始进行基本的治疗。在认知提升、疾病检测、干预措施以及真正落实方面，我们还有很多工作要做，不仅要落实治疗方法，还要落实检测策略，这样我们才能做出治疗决策。Tuttle教授认为，这是一个全球性的问题，我们必须更好地理解为何临床实践中存在如此严重的临床惰性。

此外，除了开始治疗的问题，很多时候药物一旦停用就不会再重新启用。因此，我们还需要在维持治疗方面下功夫。如果我们需要停用某种药物，那么应该停用的是那些对患者无益的“垃圾药物”，而不是那些能够挽救肾脏、心脏和生命的药物。

Nephrology On-line: Looking ahead, what are the most urgent clinical or research questions that need to be addressed in the next phase of managing diabetic kidney disease？

Dr Tuttle: I think implementation now is the next frontier on the clinical side. But again, it's a welcome conversation, because five years ago, when we didn't have any therapies, it wasn't a discussion point because there was nothing to implement. We haven't done this before because we haven't had treatment. So, hooray! Now we have to learn how to do that. But it is concerning that we have these highly effective therapies yet real-world datasets show even traditional ACE inhibitors and ARBs are usually used in 50% or less of people with diabetes and CKD, where we actually have the clearest evidence. So, I think that having availability of electronic records has really taught us that we are not doing as well as we thought we were doing. And that is not only in terms of treatments, but awareness and detection. Albuminuria screening in diabetes on an annual basis is less than 50%, sometimes as low as 10%. We have to first diagnose the disease and then we need to get on board with at least getting the basic treatment started. There is a lot of work to be done in terms of awareness, detection and intervention and really implementing, not only treatments, but testing strategies, so that we can get to the point of making a treatment decision. 

I think that this is a worldwide issue, and we need to understand better why there is such clinical inertia. Another thing besides just initiating therapies, many times these medicines are stopped, and they are not restarted. We also need to work on maintenance of therapies. If we need to get rid of a drug, get rid of the junk drugs they are on, not the drugs that are saving kidneys, hearts, and lives. 

精准医学的未来：从分子靶点到临床应用

Tuttle教授认为，从科学角度，当前治疗复兴的时代为精准医疗敞开了大门。

如今，我们已拥有明确的治疗靶点，相关研究正从多维度深入展开 —— 从肾脏活检的分子层面分析、单细胞转录组学研究，到借助大数据与人工智能技术进行患者风险分层，旨在精准识别对特定治疗敏感或不敏感的人群。具体而言，部分低风险患者可能仅需ACEI即可实现病情控制，这让我们能够将资源聚焦于高风险人群 —— 他们往往需要更强化或差异化的治疗方案。此外，常见疾病中还存在一类特殊群体：罕见内型患者。这类人群可能对现有疗法反应不佳，但其独特的分子特征将为研发新治疗靶点提供关键线索，助力实现个体化精准干预。

Tuttle教授总结，未来研究需在两方面齐头并进：一方面，深化精准医疗的科学研究，加速向临床实践转化；另一方面，充分利用现有诊疗手段，强化疾病诊断与治疗干预的时效性，以最大程度保护肾脏、心脏等靶器官功能，挽救患者生命。

And then on the science side, what I would say is I think having this era of a therapeutic renaissance blows the door open for precision medicine. 

Now we have something to target and there is a lot of work being done on everything from the molecular level of kidney biopsies and single cell transcriptomes to big data and AI to risk-stratify people and identify people who are more likely or not likely to respond to certain treatments. Maybe there are low-risk patients who do fine on just an ACE inhibitor, and we can then focus our efforts on higher risk patients who maybe need more therapies or different therapies. Then there will be rare endotypes within common diseases who might not respond to our current therapies, but those molecular signatures will point us to new targets that we need for some specific patients. So, I think we need to work on both ends of the spectrum - on the science of precision medicine and translating that to clinical care; and then taking what we do have and doing more with it in terms of making the diagnosis and getting treatment started when we have the best chance of, again, saving kidneys, hearts, and lives.