Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants Are Associated With Similar Lower Risk of Coronary Heart Disease, Says a New Study

A study by Ference et al. published in JAMA showed that triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the investigators believe that the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.

Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. In the study, the investigators aimed to compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Brian A. Ference and his colleagues conducted mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C–lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. The study aimed to look at differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.

In this study, the odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins. A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4%women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95%CI, 68.1-71.6; P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95%CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95%CI, 13.6-14.8; P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95%CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95%CI, 0.741-0.802], P = 3.9 × 10−38 and OR, 0.773 [95%CI, 0.747-0.801], P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95%CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95%CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95%CI, 0.723-0.798], P = 7.51 × 10−20).

The investigators reported that in the Mendelian randomization analyses involving 654,783 participants, triglyceride-lowering variants in the lipoprotein lipase gene and low-density lipoprotein cholesterol (LDL-C)–lowering variants in the LDL receptor gene were associated with similar lower risk of coronary heart disease per 10-mg/dL lower level of apolipoprotein B (ApoB)–containing lipoproteins (odds ratios of 0.771 and 0.773, respectively). This meant that the clinical benefit of lower triglyceride levels was similar to the clinical benefit of lower LDL-C levels per unit difference in ApoB and could be related to the absolute reduction in ApoB-containing lipoprotein particles.

Speaking of the existing guidelines in an accompanying editorial, Dr. Eric Peterson, Duke University Medical Center stated, “All major clinical guidelines recommend treatment to lower plasma low-density lipoprotein cholesterol (LDL-C) because numerous randomized trials have demonstrated that therapies that lower LDL-C levels by reducing LDL particles through upregulation of the LDL receptor (LDLR) reduce the risk of cardiovascular events. By contrast, the guidelines do not recommend treatment to lower plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduces the risk of cardiovascular events.” When it came to the 2018 lipid guideline, he remarked, “It represents a significant and positive step forward for cardiovascular disease prevention. While no guideline is perfect, if the algorithms in these new guidelines were followed, thousands if not millions of people worldwide each year would be able to avoid CVD events. However, the uptake and translation of guidelines into practice have been historically poor. Even in the United States, which spends more on health care than any other country, more than half of all residents did not meet the 2013 less stringent lipid management guidelines recommendations. Moving forward, the United States will need to do better to improve individual and population health. Ideally, the increased use of electronic medical records, computer-aided clinical decision support, and team-based care models could assist in the appropriate application of these algorithms for management of cholesterol levels in community practice.”