---
title: "SGLT2 Inhibitors Linked to Suppression of the Sema3A/NRP1/Plexin-A1 Axis in Postmenopausal T2D Wom"
id: "pubmed-42649130"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42649130"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42649130/"
doi: "10.1111/1753-0407.70262"
published_at: "2026-09-01T00:00:00.000Z"
evidence_level: "Letter"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SGLT2 Inhibitors Linked to Suppression of the Sema3A/NRP1/Plexin-A1 Axis in Postmenopausal T2D Wom
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42649130
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42649130/)
- **DOI:** [10.1111/1753-0407.70262](https://doi.org/10.1111%2F1753-0407.70262)
- **Published At:** 2026-09-01T00:00:00.000Z
- **Evidence Rating:** Letter
## Executive GIST (TL;DR)
- Study population: postmenopausal women with type 2 diabetes; authors performed a propensity score–matched comparison of **SGLT2 inhibitor** users versus non-users. - Matching: 23 SGLT2 inhibitor users matched to 23 non-users; additional matching or covariates were not detailed in the abstract. - Primary biomarker findings: Neuropilin-1 (**NRP1**) levels were significantly lower in SGLT2 inhibitor users (74.25 vs. 87.61 ng/mL; p = 0.015). - Secondary biomarker finding: the **Sema3A/NRP1** ratio was significantly higher in users (0.14 vs. 0.12; p = 0.006), interpreted as compensatory upregulation of Sema3A in the setting of NRP1 suppression. - Conventional bone outcomes (bone turnover markers and bone density): P1NP, CTX, coupling index and DXA-derived bone mineral density (BMD) showed no significant differences between groups. - Interpretation: SGLT2 inhibitors may perturb the **Sema3A/NRP1/Plexin-A1 signaling axis** before changes are detectable by standard bone turnover markers or DXA. - Clinical significance: provides a potential mechanistic explanation for inconsistent findings in prior meta-analyses on SGLT2 inhibitor effects on bone health. - Publication details: Letter in Journal of Diabetes (2026 Sep;18(9):e70262), DOI 10.1111/1753-0407.70262; no conflicts of interest declared. - Limitations: the abstract does not supply full methodological details, duration of SGLT2 inhibitor exposure, specific agents used, or clinical fracture outcomes; those details are not reported in the abstract.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliation * 1 Department of Internal Medicine, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, Turkey. * PMID: **42649130** * PMCID: [ PMC13518368 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13518368/) * DOI: [ 10.1111/1753-0407.70262 ](https://doi.org/10.1111/1753-0407.70262) Item in Clipboard # SGLT2 Inhibitors Are Associated With Suppression of the Sema3A/NRP1/Plexin-A1 Signaling Axis in Postmenopausal Women With Type 2 Diabetes: Evidence From Propensity Score-Matched Analysis Sertas Erarslan et al. J Diabetes. 2026 Sep. Show details Display options Display options Format Abstract PubMed PMID J Diabetes Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Diabetes%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Diabetes%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42649130/) . 2026 Sep;18(9):e70262. doi: 10.1111/1753-0407.70262. ### Authors [Sertas Erarslan](https://pubmed.ncbi.nlm.nih.gov/?term=Erarslan+S&cauthor_id=42649130)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42649130/#short-view-affiliation-1 "Department of Internal Medicine, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, Turkey."), [Burcu Cosgun Bora](https://pubmed.ncbi.nlm.nih.gov/?term=Bora+BC&cauthor_id=42649130)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42649130/#short-view-affiliation-1 "Department of Internal Medicine, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, Turkey.") ### Affiliation * 1 Department of Internal Medicine, Faculty of Medicine, Kütahya Health Sciences University, Kutahya, Turkey. * PMID: **42649130** * PMCID: [ PMC13518368 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13518368/) * DOI: [ 10.1111/1753-0407.70262 ](https://doi.org/10.1111/1753-0407.70262) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Propensity score-matched comparison of 23 SGLT2 inhibitor users and 23 non-users revealed that SGLT2 inhibitor use was associated with significantly lower Neuropilin-1 (NRP1) levels (74.25 vs. 87.61 ng/mL; p = 0.015) and a higher Sema3A/NRP1 ratio (0.14 vs. 0.12; p = 0.006), indicating functional impairment of the Sema3A/NRP1/Plexin-A1 bone signaling axis with compensatory Sema3A upregulation. Classical bone turnover markers (P1NP, CTX, coupling index) and DXA-derived BMD did not significantly differ between groups. These findings suggest that SGLT2 inhibitors may perturb the Sema3A/NRP1/Plexin-A1 axis before detectable changes in conventional markers, offering a novel mechanistic perspective to explain the inconsistency between existing meta-analyses on SGLT2 inhibitor bone safety. © 2026 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement The authors declare no conflicts of interest. ## Similar articles * [ Luteolin Stimulates Proliferation and Inhibits Late Differentiation of Primary Rat Calvarial Osteoblast Induced by High-dose Dexamethasone via Sema3A /NRP1/Pleixin A1. ](https://pubmed.ncbi.nlm.nih.gov/33327910/) Zheng L.Zheng L.Curr Pharm Biotechnol. 2021;22(11):1538-1545. doi: 10.2174/1389201021666201216150442.Curr Pharm Biotechnol. 2021.PMID: 33327910 * [ Plexin-A1 and plexin-B1 specifically interact at their cytoplasmic domains. ](https://pubmed.ncbi.nlm.nih.gov/12559962/) Usui H, Taniguchi M, Yokomizo T, Shimizu T.Usui H, et al.Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31. doi: 10.1016/s0006-291x(02)02966-2.Biochem Biophys Res Commun. 2003.PMID: 12559962 * [ Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. ](https://pubmed.ncbi.nlm.nih.gov/17631638/) Müller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, Büchler P, Giese T, Büchler MW, Offermanns S, Friess H.Müller MW, et al.Int J Cancer. 2007 Dec 1;121(11):2421-33. doi: 10.1002/ijc.22949.Int J Cancer. 2007.PMID: 17631638 * [ New targets in diabetic retinopathy: addressing limitations of current treatments through the Sema3A/Nrp1 pathway. ](https://pubmed.ncbi.nlm.nih.gov/40634736/) Sivaprasad S, Cheung CMG, Gliem M, Wykoff CC, Zippel N, Ishida S, Dong Nguyen Q.Sivaprasad S, et al.Eye (Lond). 2025 Dec;39(18):3209-3217. doi: 10.1038/s41433-025-03835-w. Epub 2025 Jul 9.Eye (Lond). 2025.PMID: 40634736Free PMC article.Review. * [ Molecular basis of semaphorin-mediated axon guidance. ](https://pubmed.ncbi.nlm.nih.gov/10934324/) Nakamura F, Kalb RG, Strittmatter SM.Nakamura F, et al.J Neurobiol. 2000 Aug;44(2):219-29. doi: 10.1002/1097-4695(200008)44:2 3.0.co;2-w.J Neurobiol. 2000.PMID: 10934324Review. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42649130) ## References 1. 1. Wang J., Li X., Li Y., and Lei C., “Effects of Sodium‐Glucose Cotransporter 2 Inhibitors on Bone Metabolism in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis,” BMC Endocrine Disorders 24, no. 1 (2024): 58, 10.1186/s12902-024-01575-8. - [DOI](https://doi.org/10.1186/s12902-024-01575-8) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11040974/) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/38658986/) 2. 1. 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