Letter to the Editor: Statins as potential confounding factors to investigate the association between the use of GLP-1 receptor agonists and risk of HCC

To the editor, The glucagon-like peptide-1 (GLP-1) receptor agonists were listed as the top of Science's 2023 Breakthrough of the Year on December 15, 2023. With great interest, we read the Scandinavian cohort study to investigate the association of GLP-1 receptor agonists with serious liver events among patients with type 2 diabetes by Engström et al1 published in Hepatology in December 2023. We congratulate Engström et al for their remarkable contribution in this intriguing subject.1 No significant association was found between the use of GLP-1 receptor agonists (vs. dipeptidyl peptidase-4 inhibitors) and the risk of HCC.1 The results were consistent in the sensitivity analyses by the authors.1 However, some novel findings, regarding statins and cardiovascular disease (CVD),2–4 open a new path to reevaluate the potential biases and confounding factors. Bell et al2 found that individuals with CVD (especially for atherosclerosis) have an increased risk of developing cancer (including HCC) compared with those without CVD. Statin use is associated with reduced HCC risk, which may be attributed to the reduced risk of CVD or cirrhosis.2–4 To facilitate understanding, Figure 1 presents the potentially multidimensional relationships among statins/GLP-1 receptor agonists, CVD/cirrhosis, and HCC. As shown in Figure 1, statins are potential confounding factors to investigate the aforementioned targeted relationships. There is a possibility that the use of GLP-1 receptor agonists (vs. dipeptidyl peptidase-4 inhibitors) is significantly associated with the reduced risk of HCC when the potential statins use could be well balanced between the GLP-1 receptor agonists group and dipeptidyl peptidase-4 inhibitors group.FIGURE 1: Statins as potential confounding factors to investigate the association between use of GLP-1 receptor agonists and risk of HCC through multidimensional complex pathways. Abbreviations: DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1.The authors conducted prespecified subgroup analyses in the results section by age group (35–64 y and ≥65–84 y).1 However, the 65 age critical value setting is not an acknowledged evidence-based criterion for determining subgroups in the relevant investigation.5 Therefore, more detailed age-subgroup analyses are necessary to reduce the risk of criteria selection bias and get more convincing results. In addition, the more comprehensive subgroup analyses by different diabetes/CVD courses and medication histories are warranted to reach the ultimate truth of the association between GLP-1 receptor agonists and the risk of HCC.