Browsing by Author "Smith, William"

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    A Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Disease
    (Elsevier, 2017-01) Sugatini, Toshifumi; Agapova, Olga A.; Fang, Yifu; Berman, Alycia G.; Wallace, Joseph M.; Malluche, Hartmut H.; Faugere, Marie-Claude; Smith, William; Sung, Victoria; Hruska, Keith A.; Department of Biomedical Engineering, School of Engineering and Technology
    Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr-/- high fat–fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat–fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A–enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin–A induced osteoclastogenesis.
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    Use of SGLT2 Inhibitors Reduces Heart Failures and Hospitalization: A Multicenter, Real-World Evidence Study
    (2023-04-28) Blanco, Christopher; Garcia, Kara; Singson, Adrian; Smith, William
    BACKGROUND: New research has produced evidence to support the use of diabetic drugs to prevent heart failure (HF). However, evidence of their effect in real-world clinical practice is limited. OBJECTIVE: The objective of this study is to establish whether real-world evidence supports clinical trial findings that use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces rate of hospitalization and incidence of HF for patients with cardiovascular disease and type 2 diabetes. METHODS: This retrospective study used electronic medical records to compare rate of hospitalization and incidence of HF among 37,231 patients with cardiovascular disease and type 2 diabetes under treatment with SGLT2i, glucagon-like peptide-1 receptor agonist (GLP1-RA), both, or neither. RESULTS: Significant differences were found between medication class prescribed and number of hospitalizations (p < 0.0001) and incidence of HF (p < 0.0001). Post-hoc tests revealed reduced incidence of HF in the group treated with SGLT2i relative to GLP1-RA alone (p = 0.004) or neither of these key drugs (p < 0.001). No significant differences were observed between the group receiving both drug classes compared to SGLT2i alone. DISCUSSION: Results of this real-world analysis are consistent with clinical trial findings that SGLT2i therapy reduces incidence of HF. The findings also suggest the need for further points of research in demographic and socioeconomic status differences. CONCLUSION: Real-world evidence supports clinical trial findings of SGLT2i reducing both incidence of HF and rate of hospitalization.