{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:27:34Z","timestamp":1761863254013},"reference-count":43,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":2845,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,12,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS<\/jats:title><jats:p>We conducted an ancillary study to the National Institutes of Health\u2013sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g\/day or placebo. The primary end point was change in FMD at 6 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg\/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol\/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol\/mol; P &amp;lt; 0.001), fasting glucose by 16.1 mg\/dL (P &amp;lt; 0.001), and white blood cell count by 430 cells\/\u00b5L (P &amp;lt; 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI \u22120.86 to 2.25%]; P = 0.38) or NMD (\u22120.59% [95% CI \u22122.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg\/dL higher, respectively, and urinary albumin was 2.0 \u00b5g\/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P &amp;lt; 0.009).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.<\/jats:p><\/jats:sec>","DOI":"10.2337\/dc13-0859","type":"journal-article","created":{"date-parts":[[2013,10,16]],"date-time":"2013-10-16T04:45:59Z","timestamp":1381898759000},"page":"4132-4139","update-policy":"http:\/\/dx.doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":45,"title":["Targeting Inflammation Using Salsalate in Patients With Type 2 Diabetes: Effects on Flow-Mediated Dilation (TINSAL-FMD)"],"prefix":"10.2337","volume":"36","author":[{"given":"Allison B.","family":"Goldfine","sequence":"first","affiliation":[{"name":"Joslin Diabetes Center, Boston, Massachusetts"},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Stewart","family":"Buck","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cyrus","family":"Desouza","sequence":"additional","affiliation":[{"name":"Department of Medicine, Omaha Veterans Administration Medical Center, Omaha, Nebraska"},{"name":"Department of Medicine, University of Nebraska, Omaha, Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Tulane University, New Orleans, Louisiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yii-Der Ida","family":"Chen","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven E.","family":"Shoelson","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen A.","family":"Jablonski","sequence":"additional","affiliation":[{"name":"Biostatistics Center, George Washington University, Rockville, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Creager","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the TINSAL-FMD (Targeting Inflammation Using Salsalate in Type 2 Diabetes\u2013Flow-Mediated Dilation) Ancillary Study Team","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","published-online":{"date-parts":[[2013,11,13]]},"reference":[{"key":"2022031222202853300_B1","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1093\/eurheartj\/eht142","article-title":"Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II","volume":"34","author":"Beckman","year":"2013","journal-title":"Eur Heart J"},{"key":"2022031222202853300_B2","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1172\/JCI29069","article-title":"Inflammation and insulin resistance","volume":"116","author":"Shoelson","year":"2006","journal-title":"J Clin Invest"},{"key":"2022031222202853300_B3","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/nature01323","article-title":"Inflammation in atherosclerosis","volume":"420","author":"Libby","year":"2002","journal-title":"Nature"},{"key":"2022031222202853300_B4","doi-asserted-by":"crossref","first-page":"346","DOI":"10.7326\/0003-4819-152-6-201003160-00004","article-title":"The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial","volume":"152","author":"Goldfine","year":"2010","journal-title":"Ann Intern Med"},{"key":"2022031222202853300_B5","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1752-8062.2008.00026.x","article-title":"Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes","volume":"1","author":"Goldfine","year":"2008","journal-title":"Clin Transl Sci"},{"key":"2022031222202853300_B6","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2337\/dc07-1338","article-title":"Salsalate improves glycemia and inflammatory parameters in obese young adults","volume":"31","author":"Fleischman","year":"2008","journal-title":"Diabetes Care"},{"key":"2022031222202853300_B7"},{"key":"2022031222202853300_B8","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1056\/NEJM199007053230105","article-title":"Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension","volume":"323","author":"Panza","year":"1990","journal-title":"N Engl J Med"},{"key":"2022031222202853300_B9","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1172\/JCI114688","article-title":"Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans","volume":"86","author":"Creager","year":"1990","journal-title":"J Clin Invest"},{"key":"2022031222202853300_B10","doi-asserted-by":"crossref","first-page":"H2392","DOI":"10.1152\/ajpheart.00403.2003","article-title":"Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus","volume":"285","author":"Beckman","year":"2003","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2022031222202853300_B11","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1161\/01.CIR.0000112565.60887.1E","article-title":"Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study","volume":"109","author":"Benjamin","year":"2004","journal-title":"Circulation"},{"key":"2022031222202853300_B12","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/0735-1097(95)00327-4","article-title":"Close relation of endothelial function in the human coronary and peripheral circulations","volume":"26","author":"Anderson","year":"1995","journal-title":"J Am Coll Cardiol"},{"key":"2022031222202853300_B13","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1016\/S0735-1097(03)00333-4","article-title":"Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease","volume":"41","author":"Gokce","year":"2003","journal-title":"J Am Coll Cardiol"},{"key":"2022031222202853300_B14","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1161\/CIRCULATIONAHA.109.864801","article-title":"Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis","volume":"120","author":"Yeboah","year":"2009","journal-title":"Circulation"},{"key":"2022031222202853300_B15","first-page":"1","article-title":"Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial","volume-title":"Ann Intern Med","author":"Goldfine","year":"2013"},{"key":"2022031222202853300_B16","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0735-1097(01)01746-6","article-title":"Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force","volume":"39","author":"Corretti","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"2022031222202853300_B17","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/S0002-9149(96)00597-8","article-title":"Flow-induced vasodilation of the human brachial artery is impaired in patients &lt;40 years of age with coronary artery disease","volume":"78","author":"Lieberman","year":"1996","journal-title":"Am J Cardiol"},{"key":"2022031222202853300_B18","first-page":"65","article-title":"A simple sequentially rejective multiple test procedure","volume-title":"Scand J Stat","author":"Holm","year":"1979"},{"key":"2022031222202853300_B19","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1161\/01.RES.0000269183.13937.e8","article-title":"Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB","volume":"100","author":"Donato","year":"2007","journal-title":"Circ Res"},{"key":"2022031222202853300_B20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1161\/CIRCULATIONAHA.112.127514","article-title":"Protein kinase C-\u03b2 contributes to impaired endothelial insulin signaling in humans with diabetes mellitus","volume":"127","author":"Tabit","year":"2013","journal-title":"Circulation"},{"key":"2022031222202853300_B21","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1161\/CIRCULATIONAHA.108.804294","article-title":"Nuclear factor-kappaB activation contributes to vascular endothelial dysfunction via oxidative stress in overweight\/obese middle-aged and older humans","volume":"119","author":"Pierce","year":"2009","journal-title":"Circulation"},{"key":"2022031222202853300_B22","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1161\/01.CIR.0000164260.82417.3F","article-title":"Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans","volume":"111","author":"Landmesser","year":"2005","journal-title":"Circulation"},{"key":"2022031222202853300_B23","first-page":"1432","article-title":"Comparison of effects of losartan, irbesartan, and candesartan on flow-mediated brachial artery dilation and on inflammatory and thrombolytic markers in patients with systemic hypertension","volume-title":"Am J Cardiol","author":"Koh","year":"2004"},{"key":"2022031222202853300_B24","first-page":"491","article-title":"Nifedipine improves endothelial function: role of endothelial progenitor cells","volume-title":"Hypertension","author":"Sugiura","year":"2008"},{"key":"2022031222202853300_B25","first-page":"714","article-title":"A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance","volume-title":"Diabetologia","author":"Goldfine","year":"2013"},{"key":"2022031222202853300_B26","first-page":"252","article-title":"Short term effects of infliximab on the lipid profile in patients with rheumatoid arthritis","volume":"32","author":"Vis","year":"2005","journal-title":"J Rheumatol"},{"key":"2022031222202853300_B27","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00296-009-1303-y","article-title":"Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis","volume":"31","author":"Kawashiri","year":"2011","journal-title":"Rheumatol Int"},{"key":"2022031222202853300_B28","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1016\/S0002-9149(02)02366-4","article-title":"Comparison of numbers of circulating blood monocytes in men grouped by body mass index (&lt;25, 25 to &lt;30, &gt; or =30)","volume":"89","author":"Kullo","year":"2002","journal-title":"Am J Cardiol"},{"key":"2022031222202853300_B29","first-page":"455","article-title":"High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes","volume-title":"Diabetes","author":"Vozarova","year":"2002"},{"key":"2022031222202853300_B30","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1016\/S0140-6736(99)01046-6","article-title":"Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study","volume":"353","author":"Schmidt","year":"1999","journal-title":"Lancet"},{"key":"2022031222202853300_B31","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.annepidem.2004.08.009","article-title":"Counts of neutrophils, lymphocytes, and monocytes, cause-specific mortality and coronary heart disease: the NHANES-I epidemiologic follow-up study","volume":"15","author":"Gillum","year":"2005","journal-title":"Ann Epidemiol"},{"key":"2022031222202853300_B32","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1001\/jama.1985.03360140090031","article-title":"Prognostic importance of the white blood cell count for coronary, cancer, and all-cause mortality","volume":"254","author":"Grimm","year":"1985","journal-title":"JAMA"},{"key":"2022031222202853300_B33","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1111\/j.1365-2796.2007.01864.x","article-title":"Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study","volume":"262","author":"Rana","year":"2007","journal-title":"J Intern Med"},{"key":"2022031222202853300_B34","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1126\/science.1061620","article-title":"Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta","volume":"293","author":"Yuan","year":"2001","journal-title":"Science"},{"key":"2022031222202853300_B35","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1126\/science.8052854","article-title":"Inhibition of NF-kappa B by sodium salicylate and aspirin","volume":"265","author":"Kopp","year":"1994","journal-title":"Science"},{"key":"2022031222202853300_B36","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.4049\/jimmunol.156.10.3961","article-title":"Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration","volume":"156","author":"Pierce","year":"1996","journal-title":"J Immunol"},{"key":"2022031222202853300_B37","doi-asserted-by":"crossref","first-page":"33097","DOI":"10.1074\/jbc.R500010200","article-title":"Heat shock response modulators as therapeutic tools for diseases of protein conformation","volume":"280","author":"Westerheide","year":"2005","journal-title":"J Biol Chem"},{"key":"2022031222202853300_B38","doi-asserted-by":"crossref","first-page":"5721","DOI":"10.4049\/jimmunol.173.9.5721","article-title":"A new pharmacological effect of salicylates: inhibition of NFAT-dependent transcription","volume":"173","author":"Aceves","year":"2004","journal-title":"J Immunol"},{"key":"2022031222202853300_B39","doi-asserted-by":"crossref","first-page":"24944","DOI":"10.1074\/jbc.M300423200","article-title":"Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases","volume":"278","author":"Gao","year":"2003","journal-title":"J Biol Chem"},{"key":"2022031222202853300_B40","doi-asserted-by":"crossref","first-page":"5608","DOI":"10.4049\/jimmunol.163.10.5608","article-title":"Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes","volume":"163","author":"Stevenson","year":"1999","journal-title":"J Immunol"},{"key":"2022031222202853300_B41","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1073\/pnas.94.7.2869","article-title":"Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase\/stress-activated protein kinase activation","volume":"94","author":"Schwenger","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031222202853300_B42","first-page":"790","article-title":"Salicylate downregulates 11beta-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization","volume-title":"Diabetes","author":"Nixon","year":"2012"},{"key":"2022031222202853300_B43","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1126\/science.1215327","article-title":"The ancient drug salicylate directly activates AMP-activated protein kinase","volume":"336","author":"Hawley","year":"2012","journal-title":"Science"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/36\/12\/4132\/614988\/4132.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/36\/12\/4132\/614988\/4132.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T18:25:01Z","timestamp":1716056701000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/36\/12\/4132\/33197\/Targeting-Inflammation-Using-Salsalate-in-Patients"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,13]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,11,13]]},"published-print":{"date-parts":[[2013,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc13-0859","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"type":"print","value":"0149-5992"},{"type":"electronic","value":"1935-5548"}],"subject":[],"published":{"date-parts":[[2013,11,13]]}}}