Understanding Cancer Therapy-Related Cardiac Dysfunction
Cancer therapy-related cardiac dysfunction (CTRCD) is an increasingly recognized consequence of many life-saving cancer treatments. Defined as a drop in left ventricular ejection fraction (LVEF) greater than 10%, often with symptoms of heart failure (HF), CTRCD affects 5–25% of cancer patients depending on therapy type and individual risk factors. As cancer survival improves, more patients are living long enough to experience the delayed consequences of treatment, including heart damage.
Several anticancer drugs can harm the heart. Anthracyclines, widely used in both hematologic and solid tumors, are known for their dose-dependent cardiotoxicity. Other agents, such as gonadotropin-releasing hormone agonists (used in prostate and breast cancers) and immune checkpoint inhibitors (ICIs), have also been linked to cardiovascular complications, including myocarditis. While these therapies remain critical for cancer control, their cardiac effects create a pressing need for strategies that preserve heart health without compromising cancer outcomes.
A New Role for SGLT2 Inhibitors?
Sodium-glucose co-transporter-2 (SGLT2) inhibitors were originally developed to manage type 2 diabetes. However, research has shown they also benefit the heart and kidneys, even in non-diabetic patients. SGLT2 inhibitors improve cardiac energy use, reduce inflammation and oxidative stress, and counter harmful cardiac remodeling.
These properties have led researchers to explore whether SGLT2 inhibitors can reduce the risk of CTRCD in cancer patients. While earlier meta-analyses were limited by small sample sizes and inconsistent study designs, several recent studies have offered new evidence worth evaluating.
What This Meta-Analysis Found
In a new meta-analysis published in Biomolecules and Biomedicine, Zhitao Yan and colleagues assessed whether SGLT2 inhibitors are associated with a reduced risk of CTRCD. Their analysis pooled data from 10 cohort studies involving 34,847 cancer patients, covering a range of cancer types and treatment regimens.
The researchers found that SGLT2 inhibitor use was linked to a 53% lower risk of CTRCD (risk ratio [RR]: 0.47; 95% confidence interval: 0.33–0.68). This result was consistent across various sensitivity tests.
Notably, the protective effect was strongest in patients treated with anthracyclines (RR: 0.26), a group with well-established cardiotoxic risk. In contrast, patients receiving other cancer therapies showed a more modest benefit (RR: 0.73). Subgroup analyses also revealed that the benefit was more pronounced in studies with fewer men (<55%) (RR: 0.27) than in those with a higher proportion of men (RR: 0.75), although the authors noted this could reflect differences in study characteristics and requires further investigation.
Mechanisms Behind the Effect
The authors suggest that SGLT2 inhibitors’ benefit in CTRCD may be due to their impact on several known pathways involved in heart damage from cancer treatment. One such mechanism is the improvement of cardiac energetics: these drugs help shift the heart’s energy source from glucose to fatty acids and ketone bodies, enhancing ATP production under stress.
CTRCD is also linked to oxidative stress and inflammation—especially with anthracyclines, which generate harmful reactive oxygen species (ROS) that damage mitochondria and lead to cell death. SGLT2 inhibitors may help by reducing ROS production and promoting mitochondrial repair. Additionally, their antifibrotic actions could prevent long-term structural changes in the heart.
Do Other Heart Medications Matter?
Interestingly, the cardioprotective effect of SGLT2 inhibitors remained significant regardless of whether patients were also taking angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or statins—drugs commonly used to reduce cardiovascular risk.
This independence suggests that SGLT2 inhibitors may offer unique benefits, potentially adding value even when standard cardioprotective agents are in use.
Study Strengths and Limitations
This meta-analysis is the largest to date on this topic, including data from recent high-quality observational studies. The authors followed PRISMA guidelines and conducted rigorous sensitivity and subgroup analyses. The quality of the included studies was generally good, with Newcastle-Ottawa Scale (NOS) scores ranging from seven to eight.
That said, the findings must be interpreted with caution. All included studies were observational—nine retrospective and one prospective—meaning they can identify associations but not prove causality. The authors note potential confounding by unmeasured variables, such as exact cancer drug dosages or variations in SGLT2 inhibitor protocols (e.g., timing or dose). Most studies included patients with diabetes, which may limit generalizability to non-diabetic populations.
Implications for Clinical Practice
SGLT2 inhibitors are already approved for treating heart failure, chronic kidney disease, and type 2 diabetes. This new evidence suggests they could be repurposed to protect the heart in cancer patients, particularly those receiving anthracyclines. Because many cancer patients have overlapping cardiovascular risks, the dual benefit of metabolic and cardiac protection makes these drugs especially appealing.
However, the observational nature of current evidence means randomized controlled trials (RCTs) are needed before changes in clinical practice can be recommended. The study authors did not comment further on future trials, but their findings may encourage trial design aimed at testing SGLT2 inhibitors as a preventative option in high-risk cancer populations.
A Step Toward Safer Cancer Treatment
As the cancer population ages and survival improves, managing long-term complications like CTRCD becomes increasingly important. This study contributes valuable data suggesting that SGLT2 inhibitors might play a role in addressing this unmet need.
While more research is needed, these findings support the idea that cardiometabolic medications can do more than manage chronic disease—they may also protect vulnerable organs during aggressive therapies.
The translation of the preceding English text in Chinese:
理解癌症治疗相关的心脏功能障碍
癌症治疗相关的心脏功能障碍（CTRCD）是许多挽救生命的癌症治疗日益被认识到的一种后果。CTRCD 被定义为左心室射血分数（LVEF）下降超过 10%，通常伴有心力衰竭（HF）的症状，根据治疗类型和个体风险因素的不同，其影响了 5% 到 25% 的癌症患者。随着癌症生存率的提高，越来越多的患者活得足够久，以致于出现治疗的延迟性副作用，包括心脏损伤。
多种抗癌药物可能会对心脏造成伤害。蒽环类药物广泛应用于血液系统和实体肿瘤中，以其剂量依赖性的心脏毒性而著称。其他药物，如促性腺激素释放激素激动剂（用于前列腺癌和乳腺癌）和免疫检查点抑制剂（ICIs）也与心血管并发症有关，包括心肌炎。虽然这些治疗对控制癌症至关重要，但它们的心脏影响促使我们迫切需要在不影响癌症治疗效果的前提下保护心脏健康的策略。
SGLT2 抑制剂的新角色？
钠-葡萄糖共转运蛋白2（SGLT2）抑制剂最初用于治疗2型糖尿病。然而，研究发现，即使在非糖尿病患者中，这些药物也有益于心脏和肾脏健康。SGLT2 抑制剂可改善心脏能量代谢，减少炎症和氧化应激，并抑制有害的心脏重构。
这些特性促使研究人员探索 SGLT2 抑制剂是否能降低癌症患者发生 CTRCD 的风险。虽然早期的荟萃分析因样本量小和研究设计不一致而受到限制，但近期几项研究提供了值得评估的新证据。
这项荟萃分析发现了什么
在《Biomolecules and Biomedicine》发表的一项新荟萃分析中，Zhitao Yan 等人评估了 SGLT2 抑制剂是否与 CTRCD 风险降低相关。他们汇总了10项队列研究的数据，涵盖34,847名癌症患者，涉及多种癌症类型和治疗方案。
研究发现，使用 SGLT2 抑制剂与 CTRCD 风险降低 53% 相关（风险比 [RR]：0.47；95% 置信区间：0.33–0.68）。这一结果在各种敏感性测试中均保持一致。
值得注意的是，该保护效应在接受蒽环类药物治疗的患者中最为显著（RR：0.26），而这类药物的心脏毒性风险最为明确。相比之下，接受其他癌症治疗的患者仅表现出适度的益处（RR：0.73）。亚组分析还显示，在男性比例较低的研究中（<55%）观察到更明显的益处（RR：0.27），而男性比例较高的研究中为 RR：0.75，作者指出这可能反映了研究特征的差异，需进一步探讨。
潜在机制
作者认为 SGLT2 抑制剂在 CTRCD 中的益处可能归因于其对癌症治疗相关心脏损伤路径的影响。其中一个机制是改善心脏能量代谢：这些药物将心脏的能量来源从葡萄糖转为脂肪酸和酮体，从而在压力下增强 ATP 的生成。
CTRCD 也与氧化应激和炎症相关，尤其是蒽环类药物会产生有害的活性氧（ROS），损害线粒体并导致细胞死亡。SGLT2 抑制剂可能通过减少 ROS 产生和促进线粒体修复发挥作用。此外，其抗纤维化作用可能有助于防止心脏结构发生长期改变。
其他心脏药物是否有影响？
有趣的是，无论患者是否同时服用血管紧张素转化酶抑制剂（ACEI）、血管紧张素 II 受体阻断剂（ARB）或他汀类药物（常用于降低心血管风险），SGLT2 抑制剂的心脏保护效应依然显著。
这说明 SGLT2 抑制剂可能具有独特的作用机制，即便在标准心脏保护药物联合使用的背景下仍具有附加价值。
研究优点与局限性
这是迄今为止该主题最大规模的荟萃分析，包含了近期高质量观察性研究的数据。作者遵循了 PRISMA 指南，进行了严格的敏感性和亚组分析。所纳入研究的质量总体良好，Newcastle-Ottawa 评分为7到8分。
不过，结果需谨慎解读。所有研究均为观察性研究——其中九项为回顾性，一项为前瞻性——只能发现关联，无法证明因果关系。作者指出可能存在未测量变量的混杂因素，如具体抗癌药物剂量或 SGLT2 抑制剂的使用方案（如起始时间或剂量）差异。大多数研究包括糖尿病患者，因此结果的可推广性对非糖尿病人群可能有限。
临床实践启示
SGLT2 抑制剂已被批准用于治疗心力衰竭、慢性肾病和2型糖尿病。这项新证据表明，它们可能可用于癌症患者的心脏保护，尤其是在接受蒽环类治疗的人群中。由于许多癌症患者同时存在心血管风险因素，其代谢与心脏双重保护的优势使该药物极具吸引力。
然而，由于现有证据大多来自观察性研究，尚需进一步开展随机对照试验（RCT）以支持临床实践的改变。尽管作者未详细讨论未来的试验方向，但他们的发现可能为未来设计验证 SGLT2 抑制剂作为癌症高风险人群预防选项的研究提供依据。
迈向更安全的癌症治疗
随着癌症患者的老龄化和生存时间延长，如何应对 CTRCD 等长期并发症变得愈发重要。本研究为探索 SGLT2 抑制剂在此方面的潜力提供了有价值的数据。
尽管仍需更多研究，但这些发现支持这样一个理念：心代谢药物不仅能管理慢性病，还可能在激进治疗过程中保护易受损的器官。
Reference:
Zhitao Yan, Xiaona Xing, Jinmei Huang
The influence of sodium-glucose co-transporter-2 inhibitors on the risk of cancer therapy-related cardiac dysfunction: A meta-analysis. Biomol Biomed [Internet]. 2025 Mar. 10 [cited 2025 May 15];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11847
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