Characterisation of triglyceride changes and cardiotoxicity during fluoropyrimidine therapy

Background Fluoropyrimidines are cornerstones in treating gastrointestinal malignancies but may cause cardiotoxicity. Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), has also been linked to hypertriglyceridaemia (HTG), though incidence, magnitude and clinical impact remain poorly defined. Better characterisation of treatment-related triglyceride (TG) changes may inform cardiovascular risk management. Purpose To evaluate capecitabine versus 5-FU on serum TG, identify predictors of HTG, and determine whether TG rises are associated with fluoropyrimidine-associated cardiotoxicity (FAC). Methods In this prospective, two-centre observational cohort study, consecutive gastrointestinal cancer patients were enrolled prior to capecitabine- or 5-FU-based chemotherapy. Lipids were measured at baseline, post-cycle 1, and treatment completion. HTG was categorised using European Atherosclerosis Society (EAS) criteria. FAC was adjudicated using prespecified clinical definitions. Longitudinal changes were analysed using mixed modelling and transition matrices. Results In 413 patients (mean age 62±11 years; 40% female; 33% on statins), median baseline TG was 1.42 (IQR 1.03-1.68) mmol/L; 37% had HTG. 53% received capecitabine, 47% 5-FU, with no difference in baseline lipid profiles. Post-cycle 1, TG increased in capecitabine-treated patients but not in those receiving 5-FU. Mixed modelling showed a greater mean TG rise with capecitabine (+0.54 mmol/L) than 5-FU (+0.10 mmol/L; p=0.006). At treatment completion, TG levels were not significantly different from baseline in either group. 37.3% of patients had moderate and 1.2 % had severe HTG post-cycle 1. There was 1 case of extreme HTG (TG = 39.32 mmol/L). Between baseline and post-cycle 1 , 32% of patients with optimal TGs developed HTG, and 4.3% with moderate HTG progressed to severe HTG. 57% of those with moderate HTG at cycle 1 remained elevated at completion. Capecitabine was associated with greater increase in severity of HTG grade than 5-FU post-cycle 1 (32.6% vs 18.7% p <0.001). TG changes were not associated with capecitabine dose intensity, statin therapy, diabetes, BMI, or other cardiometabolic factors. Other lipid parameters were unchanged, except for a reduction in LDL from baseline to cycle 1 (2.45 to 2.00 mmol/L, p<0.001). During median follow-up of 424 (IQR 208–720) days, 28 patients (6.8%) developed coronary type FAC. Neither absolute TG rise, baseline TG or worsening TG category was associated with increased odds of cardiotoxicity. Conclusions Capecitabine is commonly associated with an early, reversible rise in TGs verus 5-FU, independent of metabolic risk factors or statin use. Despite frequent transient worsening in TG category, these changes were not associated with cardiotoxicity in this cohort. Routine lipid monitoring may help characterise metabolic effects of therapy, but longer studies are needed to determine long-term cardiovascular implications.