PMID- 34275349 OWN - NLM STAT- MEDLINE DCOM- 20211006 LR - 20211006 IS - 1752-8984 (Electronic) IS - 1479-1641 (Print) IS - 1479-1641 (Linking) VI - 18 IP - 4 DP - 2021 Jul-Aug TI - The relationship of neutrophil elastase and proteinase 3 with risk factors, and chronic complications in type 2 diabetes: A Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) sub-study. PG - 14791641211032547 LID - 10.1177/14791641211032547 [doi] LID - 14791641211032547 AB - INTRODUCTION: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. METHODS: Plasma NE and PR3 levels were quantified at baseline (n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels (n = 200) were determined at four follow-up visits. RESULTS: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. CONCLUSIONS: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate. FAU - Ong, Kwok-Leung AU - Ong KL AUID- ORCID: 0000-0001-7229-7614 AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. AD - Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. FAU - Wu, Liang AU - Wu L AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. AD - Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. FAU - Januszewski, Andrzej S AU - Januszewski AS AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - O'Connell, Rachel AU - O'Connell R AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - Xu, Aimin AU - Xu A AD - Department of Medicine, University of Hong Kong, Hong Kong, China. AD - State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China. FAU - Scott, Russell S AU - Scott RS AD - Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand. FAU - Sullivan, David R AU - Sullivan DR AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. AD - Department of Chemical Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. FAU - Rye, Kerry-Anne AU - Rye KA AD - Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. FAU - Li, Huating AU - Li H AD - Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. FAU - Ma, Ronald Cw AU - Ma RC AD - Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. AD - Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China. AD - Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. FAU - Li, Liping AU - Li L AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - Gebski, Val AU - Gebski V AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - Jenkins, Alicia J AU - Jenkins AJ AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. FAU - Jia, Weiping AU - Jia W AD - Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center of Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. FAU - Keech, Anthony C AU - Keech AC AD - NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. AD - Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Diab Vasc Dis Res JT - Diabetes & vascular disease research JID - 101234011 RN - 0 (Biomarkers) RN - 0 (Hypolipidemic Agents) RN - 0 (Inflammation Mediators) RN - 0 (Lipids) RN - EC 3.4.21.37 (ELANE protein, human) RN - EC 3.4.21.37 (Leukocyte Elastase) RN - EC 3.4.21.76 (Myeloblastin) RN - U202363UOS (Fenofibrate) SB - IM MH - Aged MH - Biomarkers/blood MH - Diabetes Mellitus, Type 2/blood/complications/diagnosis/*drug therapy MH - Female MH - Fenofibrate/adverse effects/*therapeutic use MH - Humans MH - Hypolipidemic Agents/adverse effects/*therapeutic use MH - Inflammation Mediators/*blood MH - Leukocyte Elastase/*blood MH - Lipids/blood MH - Male MH - Middle Aged MH - Myeloblastin/*blood MH - Time Factors MH - Treatment Outcome PMC - PMC8481737 OTO - NOTNLM OT - Cardiovascular disease OT - diabetes OT - microvascular disease OT - neutrophil elastase OT - proteinase 3 OT - serine protease COIS- Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Fournier Pharma (now part of Abbott Pharmaceuticals) sponsored the FIELD trial but had no role in data collection, analyses or interpretation. AJJ has served as a diabetes advisory panel member for Abbott, Medtronic and Sanofi, has received remuneration for lectures from Novo and has received peer-reviewed research support from Abbott and Medtronic. ACK has served as an Advisory Board member for Amgen, Bayer and Sanofi, and has received speaker and/or advisor honoraria from Abbott, Astra-Zeneca and Pfizer, research support from Mylan, Novartis and Sanofi and honoraria from Abbott and Amgen. RCM has received research grants for clinical trials from AstraZeneca, Bayer, MSD, Novo Nordisk, Sanofi and Tricida, and honoraria for consultancy or lectures from AstraZeneca and Boehringer Ingelheim. All other authors declare no conflict of interest. EDAT- 2021/07/20 06:00 MHDA- 2021/10/07 06:00 PMCR- 2021/07/17 CRDT- 2021/07/19 05:25 PHST- 2021/07/19 05:25 [entrez] PHST- 2021/07/20 06:00 [pubmed] PHST- 2021/10/07 06:00 [medline] PHST- 2021/07/17 00:00 [pmc-release] AID - 10.1177_14791641211032547 [pii] AID - 10.1177/14791641211032547 [doi] PST - ppublish SO - Diab Vasc Dis Res. 2021 Jul-Aug;18(4):14791641211032547. doi: 10.1177/14791641211032547.