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A pathological feature of insulin resistance is impaired endothelial function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the effect of FFA reduction with either acipimox, a nicotinic acid derivative that impairs lipolysis, or salsalate, a salicylate that reduces basal and inflammation\u2010induced lipolysis, on insulin\u2010mediated endothelium\u2010dependent vasodilation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a post hoc, combined analysis of two randomised, double\u2010blind, placebo\u2010controlled crossover trials. Sixteen subjects were recruited (6 with metabolic syndrome and 10 controls) and randomised to acipimox 250\u2009mg orally every 6\u2009h for 7\u2009days or placebo. Nineteen subjects were recruited (13 with metabolic syndrome and 6 controls) and randomised to receive salsalate 4.5\u2009g\/day for 4\u2009weeks or placebo. The primary outcome was the association between FFA concentration and insulin\u2010mediated vasodilation, measured by venous\u2010occlusion strain\u2010gauge plethysmography at baseline and following FFA modulation with the study drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, FFA concentration (<jats:italic>R<\/jats:italic>\u2009=\u2009\u22120.35, <jats:italic>p<\/jats:italic>\u2009=\u20090.043) and insulin sensitivity (HOMA\u2010IR: <jats:italic>R<\/jats:italic>\u2009=\u2009\u22120.42, <jats:italic>p<\/jats:italic>\u2009=\u20090.016, Adipo\u2010IR: <jats:italic>R<\/jats:italic>\u2009=\u2009\u22120.39, <jats:italic>p<\/jats:italic>\u2009=\u20090.025) predicted insulin\u2010mediated vasodilation. FFA levels were significantly reduced after drug pretreatment (0.604 vs. 0.491\u2009mmol\/L, <jats:italic>p<\/jats:italic>\u2009=\u20090.036) while insulin levels, insulin sensitivity and inflammatory markers were unchanged. Despite a reduction in circulating FFA with drug therapy, neither insulin\u2010stimulated vasodilation nor insulin sensitivity improved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Short\u2010term reduction of FFA concentration does not improve insulin\u2010stimulated vasodilation in patients with metabolic syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/\">ClinicalTrials.gov<\/jats:ext-link> identifier: NCT00759291 and NCT00760019 (formerly NCT00762827)<\/jats:p><\/jats:sec>","DOI":"10.1002\/edm2.70031","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T17:41:01Z","timestamp":1738345261000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of Serum Free Fatty Acids in Endothelium\u2010Dependent Microvascular Function"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1755-0055","authenticated-orcid":false,"given":"Alexander E.","family":"Sullivan","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meaghan C. S.","family":"Courvan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Colorado  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron W.","family":"Aday","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Wasserman","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Niswender","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Department of Veteran Affairs Tennessee Valley Healthcare System  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Shardelow","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center Program for Metabolic Bone Disorders  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily K.","family":"Wells","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinn 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