Urinary liver-type fatty acid binding protein is an independent predictor of stroke and mortality in individuals with type 1 diabetes
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In type 1 diabetes, cardiovascular disease (CVD) and diabetic nephropathy progress in parallel, thereby potentiating the risk of premature death during their development. Since urinary liver-type fatty acid binding protein (L-FABP) predicts the progression of diabetic nephropathy, the aim of this study was to investigate whether urinary L-FABP also predicts cardiovascular outcomes and mortality.
We tested our hypothesis in a Finnish cohort of 2329 individuals with type 1 diabetes and a median follow-up of 14.1 years. The L-FABP to creatinine ratio was determined from baseline urine samples. The predictive value of urinary L-FABP was evaluated using Cox regression models, while its added predictive benefit for cardiovascular outcomes and mortality was evaluated using a panel of statistical indexes.
Urinary L-FABP predicted incident stroke independently of traditional risk factors (HR 1.33 [95% CI 1.20, 1.49]) and after further adjustment for eGFR (HR 1.28 [95% CI 1.14, 1.44]) or AER (HR 1.24 [95% CI 1.06, 1.44]). In addition, it predicted mortality independently of traditional risk factors (HR 1.34 [95% CI 1.24, 1.45]), and after adjustment for eGFR (HR 1.29 [95% CI 1.18, 1.39]) or AER (HR 1.22 [95% CI 1.09, 1.36]). Urinary L-FABP was as good a predictor as eGFR or AER, and improved the AUC for both outcomes on top of traditional risk factors, with no reclassification benefit (integrated discrimination improvement/net reclassification improvement) for stroke or mortality when AER or eGFR were added to traditional risk factors. However, urinary L-FABP was not a predictor of other cardiovascular endpoints (coronary artery disease, peripheral vascular disease and overall CVD events) when adjusted for the AER.
Urinary L-FABP is an independent predictor of stroke and mortality in individuals with type 1 diabetes.
KeywordsCardiovascular disease Diabetic complications Liver-type fatty acid binding protein Mortality Stroke Type 1 diabetes Urinary biomarkers Urinary L-FABP
Coronary artery disease
End-stage renal disease
Integrated discrimination improvement
Liver-type fatty acid binding protein
Net reclassification improvement
Peripheral vascular disease
Receiver operating characteristic
We thank our skilled laboratory technicians M. Parkkonen, A.-R. Salonen, A. Sandelin, T. Soppela, J. Tuomikangas (Helsinki University Central Hospital), R. Sedlmaier-Prasselsperger and K. Jaensch (Roche Germany) for their excellent organisation and measurement of urine samples on the Elecsys system. Finally, we acknowledge all physicians and nurses at each centre who participated in the recruiting participants. (The complete list of physicians and nurses is provided in ESM Table 9.)
The dataset is not publicly available for reasons of patient confidentiality. Please contact the authors for more information.
The study was supported by grants from Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Foundation, Novo Nordisk Foundation, Academy of Finland, Päivikki and Sakari Sohlberg Foundation and the Finnish Medical Society (Finska Läkaresällskapet). Measurements and assays for L-FABP were partly sponsored by Roche Diagnostics. However, the sponsors were not involved in the conduct of the study. PMN was supported by an Albert Renold Fellowship from the EASD. DG was supported by the Waldemar von Frenckell Foundation, the Paulo Foundation, the Paavo Nurmi Foundation, the Finnish Medical Foundation, the Swedish Cultural Foundation in Finland, and the Dorothea Olivia, Karl Walter och Jarl Walter Perkléns Foundation.
Duality of interest
MS is an advisory board member for Medtronic in Scandinavia, and has received lecture fees from Eli Lilly, Medtronic Finland, Novartis, Novo Nordisk, Roche, Sanofi Aventis and Merck Sharp & Dohme. P-HG has received investigator-initiated research grants from Eli Lilly and Roche; is an advisory board member for Abbvie, Astra-Zeneca, Boehringer-Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi; and has received lecture fees from Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, Elo Water, Genzyme, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi. No other potential conflicts of interest relevant to this article were reported. NMP has received lecture fees from Eli Lilly.
P-HG, CF, AB, PMH, MS and NMP conceived and designed the study and designed the data analysis; CF, MS, LMT, DG, NE, VH and P-HG collected and followed up the data; NMP researched data, performed statistical analyses and wrote the manuscript; and CF, MS, LMT, DG, NE, VH, PMH and P-HG researched data, contributed to discussions, and reviewed and edited the manuscript. P-HG is the guarantor of this work and gave final approval for the decision to publish.
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