Increased Particle Size of Triglyceride Remnant Lipoproteins, but not Their Plasma Concentration or Lipid Content, Augment Risk Prediction of Incident Type 2 Diabetes: Prospective Results from ELSA-Brasil

Importance: Type 2 Diabetes (T2DM) prevention requires accurate identification of those at high risk. Plasma triglycerides are predictive for T2DM, but triglyceride remnant lipoproteins (TRL) more accurately reflect pathophysiological changes that underlie progression to T2DM, such as pancreatic steatosis and inflammation. We hypothesized that TRL-related factors could improve risk prediction for development of T2DM. Methods: We included individuals aged 35-74 years from the ELSA-Brasil cohort who had HbA1c and an oral glucose tolerance test at baseline. Regression models were used to predict incident T2DM, starting with medical history and metabolic syndrome traits, followed by TRL-related measurements (plasma concentration, particle size, cholesterol and triglyceride content). TRL features were measured by NMR spectroscopy. Discrimination was assessed with area under receiver operator curves (AUROCs) and net reclassification improvement (NRI). Results: Among 4,466 individuals at-risk, there were 368 new cases of T2DM after 3.7 (SD=0.6) years follow-up. We derived a 14-variable model with AUROC 0.849 (95%CI: 0.842-0.875). Overall TRL-related markers did not improve predictive capacity for T2DM. However, TRL particle diameter (TRLZ) increased AUROC, particularly in individuals with Hba1c<5.7% (n=3,300 and 174 cases of incident T2DM). In this subgroup, AUROC increased from 0.74 (95%CI: 0.72-0.76 – Baseline-model) to 0.80 (95%CI: 0.77-0.84 – Baseline-model + TRLZ) (p-value=0.0002) and NRI by 21.49% (95%CI: 0.5-34.5, p=0.0103). TRLZ was highly correlated with obesity, insulin resistance and inflammation in those with pre-diabetes at baseline, but less so in those with Hba1c<5.7%. Conclusions: TRL particle diameter improves prediction of T2DM, particularly in subjects with no glycemic abnormalities at baseline. Trial Registration: This study is registered with clinicaltrials.gov, NCT02320461. Funding Statement: This study was funded by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science, Technology and Innovation (Financiadora de Estudos e Projetos [Finep] and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq]). Grant numbers: 01 06 0010.00 and 01.10.0643.03 (RS); 01 06 0212.00 and 01.10.0742-00 (BA); 01 06 0300.00 and 01.12.0284.00 (ES); 01 06 0278.00 and 01 10 0746 00 (MG); 01 06 0115.00 and 01.10.0773-00 (SP); and 01 06 0071.00 and 01.11·0093.01 (RJ). LSFC and RDS are recipients of scholarships from the CNPq grants # 437413/2018-7 and # 303734/2018-3, respectivelly. ACS is a recipient of a scholarship from the CNPq grant # 301465/2017-7 and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Fapesp) grant # 13/07607-8. This study was funded in part by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Capes) and the CNPq. Declaration of Interests: RDS has received honoraria related to consulting, research and or speaker activities from: Amgen, Ache, Astra Zeneca, Esperion, Kowa, Merck, Novo-Nordisk, PTC, Pfizer, and Sanofi/Regeneron. The other authors declare that they have no conflict of interest. Ethics Approval Statement: De-identified data was used, and the research protocol was approved by the ethics committee at each institution in Brazil and by the National Research Ethics Committee.