Systematic comparison of gliflozins identifies a selective anti-calcifying effect of canagliflozin beyond canonical SGLT2 inhibition

Canagliflozin selectively reduced aortic vascular calcification in a high-phosphate diet-induced mouse model, unlike dapagliflozin or empagliflozin, across multiple vascular systems.

• Why it matters: Conflicting reports leave unclear whether gliflozin class members share anti-calcifying benefits or whether effects extend beyond canonical SGLT2 inhibition.
• What they did: The study systematically compared canagliflozin, dapagliflozin, and empagliflozin in vivo and in ex vivo/in vitro vascular models, using RNA sequencing, OsteoSense and Annexin V/propidium iodide assays, radiolabeled 2-deoxyglucose uptake, and Seahorse ATP rate analysis.
• The result: Canagliflozin partially reversed HPD-linked aortic transcriptional changes and, in mouse VSMCs, reduced calcification, osteogenic markers, proliferation, and migration while lowering glucose uptake and mitochondrial ATP production; SGLT2/1 expression was low or undetectable and SGLT1/2 or SGLT1 inhibitors did not replicate the effect.

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