Triglycerides and Residual Risk of CVD

See article vol. 32: 786-803

Low-density lipoprotein cholesterol (LDL-C) is a primary target for lipid-lowering therapy in the guidelines for the management of dyslipidemia and prevention of atherosclerotic cardiovascular disease (ASCVD) ^{1 , 2)} . However, it is well-documented that even when LDL-C levels are kept very low, a risk of CVD event persist, the phenomena known as “a residual risk” ³⁾ . Metabolic factors, such as high levels of triglyceride-rich lipoproteins (TRLs) and their remnants, observed in individuals with high triglyceride (TG) levels, are potential targets to address the residual risk for prevention of ASCVD.

Several prospective cohort studies have reported that high TG levels are associated with the risk of first-ever ASCVD in the Japanese general populations ^{4 - 6)} . One of those studies showed that the hazard ratio per 1-standard deviation higher TG level for ischemic CVD was greater in individuals with LDL-C ＜140 mg/dL than in those with LDL-C ≥ 140 mg/dL ⁶⁾ . These results indicate that hypertriglyceridemia is a predictor of ischemic CVD; however, the strength of the association between hypertriglyceridemia and ischemic CVD might differ among individuals with differing CVD risk factor profiles and estimated CVD risks.

Mizuta et al. investigated the association between TG levels and the risk for the incidence of major adverse cardiovascular events (MACE) and the interaction by prevention categories (primary or secondary) in the association, based on retrospective cohort studies using a nationwide database among Japanese workers ⁷⁾ . Using a very large number of participants, their investigation was unique in its comparison of the predictive ability of the TG level for incident MACE between primary and secondary prevention populations. The results indicated a “the lower, the better” relationship between TG levels and risk of MACE in the primary prevention population, suggesting that low TG levels, even in those with TG ＜150 mg/dL, might be desirable for the prevention of MACE. Furthermore, it also showed “the lower, the better” associations between TG groups and risk of MACE across all the estimated risk categories (i.e. low, intermediate, and high) according to the Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022 (JAS guidelines 2022) ²⁾ . Regarding secondary prevention, the authors concluded that higher TG levels were not significantly associated with an increased risk for MACE, although they suggested that maintaining TG levels according to the guideline recommendation might be important, especially for the prevention of ischemic stroke.

These results suggest that the relationship between TG levels and the risk for MACE and its subtypes differs among populations for primary and secondary prevention. However, caution is needed when interpreting and generalizing the results. First, the spline curves and point estimates in their categorical analysis among the secondary prevention population suggest that high TG levels were associated with an increased risk for MACE, although the associations did not reach statistical significance. There could be good reasons why the secondary prevention population did not reach statistical significance even though the primary prevention group did. For example, there was a considerable age difference between the primary and secondary prevention populations (mean age: 44 vs. 58 years old). It is known that the magnitude of association between a risk factor and the risk of CVD tends to diminish with increasing age ⁸⁾ . Furthermore, the percentage of individuals on statins was 86% in the secondary prevention population and only 6% in the primary prevention population. Statins are likely to overshadow or blunt the impact of TG, as the authors pointed out in their paper. Finally, the lack of a “the lower, the better” association for AMI in the secondary prevention population might have been due to the small number of events in the reference group (7 cases), which might have led to unstable estimates. In addition, most of the secondary prevention population in their study was male (92%), not necessarily generalizable to women, and all the participants were workers, thus, likely healthier than the general population.

We concur with the authors’ point that identifying the TG levels at which CVD risk is elevated is an important goal for CVD prevention. However, whether or not pharmacological TG reduction can consequently reduce CVD risk remains unclear ⁹⁾ , and current evidence suggests that ASCVD risk mediated by TG-rich lipoproteins appears to be determined by the circulating concentration of apoB-containing particles rather than their TG content ⁹⁾ . Non-high-density lipoprotein-cholesterol (HDL-C), an estimate for all apoB-containing lipoproteins, is considered a better clinical measure of atherogenic lipoproteins than TG ¹⁰⁾ . Thus, until further evidence demonstrates otherwise, it is prudent to follow the recommendations of the JAS guidelines 2022, targeting the LDL-C goal first then the non-HDL-C goal ( Fig.1 ) for ASCVD prevention.

Fig.1. The JAS guidelines 2022: Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022.

This figure was prepared by the author based on the guidelines.

Conflicts of Interest

None.