From plasma triglycerides to triglyceride metabolism: effects on mortality in the Copenhagen General Population Study

AIMS: It is unclear whether higher triglyceride metabolism per se contributes to mortality separate from elevated triglyceride-rich lipoproteins and body mass index. This study tested the hypotheses that higher triglyceride metabolism, measured as higher plasma glycerol and β-hydroxybutyrate, is associated with increased all-cause, cardiovascular, cancer, and other mortality. METHODS AND RESULTS: This study included 30 000 individuals nested within 109 751 individuals from the Copenhagen General Population Study. During a median follow-up of 10.7 years, 9897 individuals died (2204 from cardiovascular, 3366 from cancer, and 2745 from other causes), while none were lost to follow-up. In individuals with glycerol >80 µmol/L (highest fourth) vs. individuals with glycerol <52 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.31 (95% confidence interval 1.22-1.40). In individuals with β-hydroxybutyrate >154 µmol/L (highest fourth) vs. individuals with β-hydroxybutyrate <91 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (1.11-1.26). Corresponding values for higher plasma glycerol and β-hydroxybutyrate were 1.37 (1.18-1.59) and 1.18 (1.03-1.35) for cardiovascular mortality, 1.24 (1.11-1.39) and 1.16 (1.05-1.29) for cancer mortality, and 1.45 (1.28-1.66) and 1.23 (1.09-1.39) for other mortality, respectively. Results were robust to exclusion of first years of follow-up, to stratification for covariates including plasma triglycerides and body mass index, and to further adjustments. CONCLUSION: This study observed an increased risk of all-cause, cardiovascular, cancer, and other mortality with higher triglyceride metabolism. This was not explained by higher plasma triglycerides and body mass index. The hypothesis studied in the present paper should be further validated by isotope flux studies.