Hypertriglyceridaemia and cardiovascular mortality: insights from a large-scale study

This editorial refers to ‘Impact of hypertriglyceridaemia on cardiovascular mortality according to low-density lipoprotein cholesterol in a 15.6-million population’, by H.-B. Park et al., https://doi.org/10.1093/eurjpc/zwad330. Hypertriglyceridaemia (HTG) is commonly encountered in clinical practice, occurring in 15–20% of the adult population.1 Accumulating evidence points to triglyceride-rich remnant lipoproteins as playing a causal role in atherosclerotic cardiovascular disease (ASCVD), and their role as a potential drug target remains an active area of investigation.2,3 It is thought that what drives the risk association between HTG and ASCVD is the cholesterol content of remnant lipoprotein particles and an associated pro-inflammatory state.4 However, in prior studies, the association between HTG and ASCVD was substantially weakened after adjustment for major risk factors, such as low-density lipoprotein cholesterol (LDL-C) level and high-density lipoprotein cholesterol (HDL-C).5 Meanwhile, the armamentarium to lower LDL-C has expanded such that many patients at risk for ASCVD can achieve low LDL-C levels. As such, two main questions arise: (i) does the association between HTG and cardiovascular risk persist across varying LDL-C levels and (ii) is this association best investigated using a large dataset, with a very large sample size, across a wide range of LDL-C values? The paper titled ‘Impact of hypertriglyceridaemia on cardiovascular mortality according to low-density lipoprotein cholesterol in a 15.6 million population’ by Dr. Park, Dr. Yi, and colleagues dives into the association between triglyceride (TG) levels and cardiovascular disease (CVD) mortality in a South Korean population.6 An obvious strength of this study is its size. The data were extrapolated from the National Health Insurance Service in South Korea, covering 97% of the population with obligatory health insurance inclusive of biennial health screenings in individuals aged 18–99 years. The large dataset enabled the ability to stratify across various LDL-C levels, as well as by age, sex, and other factors. The study examines overall CVD mortality and mortality related to ischaemic heart disease, acute myocardial infarction, ischaemic, haemorrhagic stroke, and heart failure. The findings of this study contribute significantly to the ongoing debate surrounding HTG and its role as an independent CVD risk factor. The study reports a log-linear relationship between TG levels and overall CVD mortality, particularly ischaemic heart disease and acute myocardial infarction. This association holds across the range of TG levels, down to levels <50 mg/dL. Every two-fold increase in TG levels was associated with a 1.1-fold increase in overall CVD mortality. The association of HTG with CVD mortality was maintained even after adjusting for major CVD risk factors, including body mass index, blood pressure, diabetes, LDL-C levels, and HDL-C levels as well as behavioural and sociodemographic risk factors. Furthermore, even in individuals with LDL-C levels <100 mg/dL, the association with CVD mortality persisted, albeit to a weaker magnitude (2-fold higher TG associated with 1.05-fold higher CVD mortality). Looking at subtypes of CVD mortality, the study found relationships for endpoints that were more closely related to atherosclerotic disease, in particular ischaemic heart disease, acute myocardial infarction, and ischaemic stroke, whereas mortality related to heart failure and haemorrhagic stroke was not associated with TG levels. One key strength of this study is its inclusion of individuals with low LDL-C. About one-third of the study population had LDL-C levels <100 mg/dL (n = 5 480 875). Cardiovascular mortality risk identified in this population extended even to the youngest individuals 18–44 years of age. These findings suggest a potential cardiovascular benefit to TG management in conjunction with LDL-C lowering. However, it should be noted that in many patients at high or very high ASCVD risk, current guidelines aim for LDL-C levels <70 or <55 mg/dL, thus an LDL-C category of <100 mg/dL does not precisely address the group that is truly considered to have optimal LDL-C levels by modern standards. Furthermore, it is important to consider that this is an observational study, and thus causal inferences cannot be definitively made. Assuming causality, the authors suggest that the data can be used to support a therapeutic target for TG levels. Considering that mortality risk was clearly distinguished across the 200 mg/dL TG cutpoint, regardless of age, sex, or LDL-C levels, the authors suggest a basic TG goal of <200 mg/dL. The investigators then suggest a second TG goal of <100 mg/dL, where the lowest levels of CVD mortality are observed. We agree that the totality of evidence points to TG levels of <100 mg/dL being optimal. Nevertheless, a challenge with implementing TG goals in current clinical practice is the question of how one gets there. In general, if aiming for these lower TG levels facilitates greater adherence to guideline-recommended lifestyle habits (greater physical activity, healthier diet, and reducing alcohol intake), then such goals may be reasonable and provide value in clinical practice. Indeed, such an approach reflects the reality that HTG is mainly a lifestyle condition driven by obesity, lack of aerobic exercise/strength training, poor dietary habits, insulin resistance, and alcohol consumption. However, there is not a clear evidence-based pharmacological strategy that can be tied to such TG goals at the present time. While the results of this study suggest the importance of HTG management, previous studies have not shown a risk reduction in TG-lowering therapy. Clinical trials have failed to establish that pharmacologically lowering TG levels leads to better ASCVD outcomes. The FIELD study showed that fenofibrate did not significantly reduce the risk of primary coronary events in patients with type 2 diabetes relative to placebo.7 More recently, pemafibrate failed to improve cardiovascular outcomes through TG lowering in the PROMINENT trial.8 With respect to omega-3 fatty acid therapies, trials have provided mixed results and mostly have failed. The main study that shows the clinical benefit of TG lowering therapy is the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) trial.9 REDUCE-IT found that icosapent ethyl led to significant reductions in multiple ischaemic end points, including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina in both US and non-US subgroups. However, it does not appear that the benefit of icosapent ethyl observed in the REDUCE-IT trial can be primarily explained by its TG-lowering property. There thus remains a lot for us to learn about how we can improve the cardiovascular outcomes of patients through TG-lowering strategies. This study provides encouragement to continue on this journey, challenging the belief that HTG loses its significance once other major risk factors, especially LDL-C levels, are controlled, suggesting that HTG is indeed an independent risk factor for CVD mortality. Another interesting aspect of this study is the notion that there may be a potential benefit of managing HTG in low-risk populations, such as young adults. This is evidenced by the stronger association between TG level and CVD mortality in younger adults. This goes further to challenge the notion that HTG management is only of clinical relevance in high-risk individuals. Limitations of this study include its analysis of only a single ethnicity and geographical location, which could limit its generalizability to other regions and ethnicities. The large-scale nature of the study will hopefully inspire further large-scale studies elsewhere in the world to better understand if the results are similar or different. Another limitation of the study is the methodology used for LDL-C assessment. The analysis relied on the Friedewald equation to estimate LDL-C, however, it is now well known that this equation has a tendency to underestimate LDL-C at lower concentrations in patients with HTG. In contemporary practice, the most accurate method to determine LDL-C is the Martin-Hopkins equation for patients with TG levels <400 mg/dL, and the extended Martin-Hopkins equation for patients with TG levels 400–799 mg/dL.10 Another limitation to consider is the CVD mortality endpoints used in the study. There can be challenges in accurately assigning the cause of death and no adjudication process was specified. Future studies will ideally also evaluate expanded cardiovascular endpoints such as myocardial infarction using the universal definition and a rigorous adjudication process. Furthermore, we note that snapshot measurements of TG do not capture the day-to-day fluctuations in TG levels. TG levels are more variable over time than LDL-C, often changing significantly in relation to glycemic control, fatty meals, alcohol consumption, and other lifestyle habits. A more complete approach to consider in future studies would be assessing serial TG levels, glycemic control, and even detailed lifestyle habits via a patient-driven app or questionnaire to better understand these variations that may impact TG levels. So how should clinicians think about the data from the present study in the context of managing patients with HTG and lower ASCVD risk? First, consider that HTG is most often secondary. This paper underscores the importance of assessing secondary causes of HTG such as diet, exercise, obesity, alcohol use, and insulin resistance. Because regardless of how HTG increases CVD risk, addressing secondary factors can reduce ASCVD risk. Second, consider that the ASCVD risk associated with HTG is attenuated at lower LDL-C levels, reinforcing the guideline recommendations and expert consensus documents on treating to a low LDL-C goal with maximally tolerated statin/ezetimibe for ASCVD benefit. If there is persistent HTG despite optimizing LDL-C levels, consider icosapent ethyl to lower ASCVD risk. Nevertheless, there is a sparseness of evidence-based medications to lower cardiovascular risk through TG lowering and future results from clinical trials of novel agents (e.g. targeting APOC3) will be illuminating. The present manuscript did not have dedicated funding.