Diabetes Drugs May Ease Pulmonary Hypertension by Taming Activin A Signaling

Some of the most celebrated drugs in modern cardiology may be doing far more than lowering blood sugar and protecting the heart’s pumping chambers. New research published in GeroScience suggests that sodium-glucose cotransporter 2 inhibitors, the widely prescribed medications better known as SGLT2 inhibitors, are associated with a striking molecular shift in patients with ischemic heart failure who are at high risk of pulmonary hypertension. The study, led by Rosalinda Madonna and Raffaele De Caterina at Pisa University Hospital together with colleagues across Italy and Hungary, reports that patients treated with these drugs showed reduced circulating levels of activin A, a signaling molecule implicated in maladaptive cardiac remodeling, alongside measurable improvements in right-heart function and a lower echocardiographic probability of pulmonary hypertension.

Pulmonary hypertension is one of the most feared complications of heart failure with reduced ejection fraction, the condition in which a damaged left ventricle can no longer pump blood efficiently. As pressure backs up into the vessels of the lungs, the right ventricle must work against rising resistance, eventually failing in its own right. Prognosis worsens sharply once this happens, yet therapeutic options remain frustratingly limited. SGLT2 inhibitors such as dapagliflozin and empagliflozin have already transformed heart failure care after large trials demonstrated reduced hospitalizations and cardiovascular deaths, and earlier work, including the EMBRACE-HF trial of empagliflozin, hinted at favorable effects on pulmonary artery pressures. What remained unclear was whether these drugs influence the pulmonary circulation through mechanisms beyond their established hemodynamic and metabolic effects.

To probe that question, the researchers prospectively enrolled seventy-four patients with ischemic heart failure following acute myocardial infarction, all of whom had a high echocardiographic probability of pulmonary hypertension. In this single-center, non-randomized study, forty-two patients received either dapagliflozin or empagliflozin at 10 milligrams per day on top of guideline-directed medical therapy, while thirty-two patients received guideline-directed therapy alone. The design means the findings show association rather than causation, but the investigators compensated by layering on an unusually deep molecular workup, including untargeted plasma proteomics on pooled samples, microRNA profiling, and selected biomarkers of cellular senescence and oxidative stress. Candidate discoveries were then validated with enzyme-linked immunosorbent assays and quantitative reverse-transcription polymerase chain reaction.

The clinical signal was consistent and encouraging. Patients on SGLT2 inhibitors showed improved World Health Organization functional class, meaning they could tolerate more physical activity before symptoms limited them. They also displayed fewer signs of right-heart failure, a reduced echocardiographic probability of pulmonary hypertension, and enhanced coupling between the right ventricle and the pulmonary artery, a key echocardiographic measure of how efficiently the right heart’s pump matches the load imposed by the lung circulation. Right ventricle-pulmonary artery coupling is increasingly recognized as a powerful prognostic marker in heart failure, and its improvement here aligns with recent secondary analyses of randomized trials suggesting that dapagliflozin favorably reshapes right ventricular-vascular interaction.

Beneath these clinical observations lay the study’s most intriguing molecular thread. Proteomic and microRNA analyses revealed that SGLT2 inhibitor therapy was associated with lower circulating activin A and reduced levels of miR-1306-5p, a small regulatory RNA previously linked to vascular smooth muscle proliferation through the SIRT7 pathway. Activin A belongs to the transforming growth factor beta superfamily, a group of signaling proteins that orchestrate tissue repair, fibrosis, and inflammation. Elevated activin A has long been documented in chronic heart failure, where it is thought to promote adverse myocardial remodeling. By contrast, bone morphogenetic protein signaling, particularly through the BMPR2 receptor, acts as a protective counterweight, and loss of BMPR2 function is a classic driver of pulmonary arterial hypertension. The balance between these opposing arms of the BMP/activin/TGF-beta axis may therefore help determine whether pulmonary vessels adapt or deteriorate under pressure.

Recognizing that a non-randomized clinical observation can only go so far, the team turned to experimental models to test whether the drug could actually drive the molecular changes they had observed. In animal models of ischemia-reperfusion injury, empagliflozin reduced activin A, increased BMPR2 expression, and improved post-ischemic ventricular function. Parallel experiments in human pulmonary artery endothelial cells and cardiomyocytes exposed to hypoxia, the low-oxygen conditions that mimic the hostile environment of failing pulmonary circulation, showed similar molecular shifts. The convergence of clinical and laboratory findings on the same signaling pathway is what gives the study its persuasive force, suggesting that activin A suppression is not an incidental biomarker but a plausible mechanistic link between the drug and the improved pulmonary phenotype.

The researchers also gained a hint about how the drug might exert these effects. When they added chloroquine, an inhibitor of autophagy, the cellular recycling process that degrades damaged components, the beneficial molecular changes were partially attenuated. This points to autophagy as a possible intermediary in the signaling cascade, consistent with earlier work by the same group showing that empagliflozin modulates excessive autophagy through the AMPK/GSK3-beta pathway in diabetic cardiomyopathy. Autophagy has emerged as a central theme in both cardiac and pulmonary vascular disease, and age-related decline in this quality-control system is one of the hallmarks of aging biology, which is precisely why the study appears in GeroScience, a journal focused on the molecular mechanisms of aging.

The findings also resonate with a broader therapeutic landscape that is shifting toward the TGF-beta superfamily. Sotatercept, a fusion protein that traps activin and related ligands, recently demonstrated impressive results in a phase 3 trial of pulmonary arterial hypertension, effectively validating activin signaling as a drug target. The new study raises the tantalizing possibility that SGLT2 inhibitors achieve a gentler version of the same effect through endogenous means, dialing down activin A production rather than sequestering the ligand after release. If confirmed, patients already taking these drugs for heart failure or diabetes might be accruing pulmonary vascular benefits that no one had fully appreciated, simply as a byproduct of a prescription they were already filling.

Important caveats remain. The clinical arm was non-randomized and single-center, with a modest sample size, so confounding by indication, disease severity, or co-treatment cannot be excluded, and the pooled proteomic design limits individual-level inference. The authors themselves frame the work as showing that modulation of the BMP/activin/TGF-beta pathway is biologically plausible and consistently associated with SGLT2 inhibitor therapy across complementary models, rather than proving it as the definitive mechanism. Still, the triangulation from patient plasma to animal hearts to hypoxic human cells is exactly the kind of convergent evidence that typically precedes randomized testing. If future trials confirm that SGLT2 inhibitors meaningfully lower pulmonary pressures and improve right-heart outcomes through activin A suppression, a drug class born as a glucose-lowering agent will have added yet another chapter to one of the most remarkable therapeutic repurposing stories in cardiovascular medicine, and patients with the doubly burdened heart-and-lung phenotype of advanced heart failure may gain a new lease on survival.

Subject of Research: SGLT2 inhibitor effects on activin A and BMP/activin signaling in ischemic cardiomyopathy with pulmonary hypertension

Article Title: Sodium-glucose cotransporter 2 inhibitors are associated with reduced circulating activin A and modulation of BMP/activin signaling in ischemic cardiomyopathy with high echocardiographic probability of pulmonary hypertension

Article References: Madonna, R., Del Boccio, P., Borghini, A., Alberti, M., Biondi, F., Cufaro, M. C., Morganti, R., Pieragostino, D., Andreassi, M. G., Rocca, C., Ferdinandy, P., Mattii, L., Angelone, T., & De Caterina, R. (2026). Sodium-glucose cotransporter 2 inhibitors are associated with reduced circulating activin A and modulation of BMP/activin signaling in ischemic cardiomyopathy with high echocardiographic probability of pulmonary hypertension. GeroScience. https://doi.org/10.1007/s11357-026-02497-0

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02497-0

Keywords: SGLT2 inhibitors, pulmonary hypertension, activin A, BMPR2, heart failure, ischemic cardiomyopathy, empagliflozin, dapagliflozin, autophagy, miR-1306-5p, right ventricle, TGF-beta signaling