More Evidence that Low-density Lipoprotein Cholesterol and Triglyceride-lowering Genetic Variants Reduce Risk of Coronary Heart Disease
By Kevin C Maki, PhD and Mary R Dicklin, PhD
The total cholesterol concentration in circulation is comprised of cholesterol carried by three main types of lipoproteins: low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL) and high-density lipoproteins (HDL). VLDL particles are the main carriers of triglycerides (TG), and the Friedewald equation estimates the VLDL cholesterol (VLDL-C) level in mg/dL as TG/5. LDL and VLDL particles each contain a single molecule of apolipoprotein B (Apo B). Non-HDL cholesterol (non-HDL-C) is the sum of the cholesterol carried by all particles that contain Apo B, i.e., LDL-C + VLDL-C. Note for purists: this ignores a quantitatively small contribution of cholesterol carried by chylomicron remnants and it includes cholesterol carried by lipoprotein (a) particles, which are generally in the LDL density range.
Non-HDL-C has been found to be a more consistent predictor of coronary heart disease (CHD) risk than LDL-C (Liu 2005, Robinson 2009). Prior studies have shown that genetic variants that modify each of the components of non-HDL-C are associated with modification of cardiovascular disease risk, particularly incidence of CHD.
Ference and colleagues recently published a large-scale analysis of data from a group of 654,783 subjects, in 63 case-control or cohort studies, to investigate two sets of lipid-lowering genetic variants for the LDL receptor gene and the lipoprotein lipase (LPL) gene that predominantly affect LDL-C and TG, respectively (Ference 2019, Navar 2019). The analysis included 91,129 cases of CHD. Their investigation showed that both genetically-induced LDL-C reduction through the LDL receptor gene score and TG reduction through the LPL gene score were associated with significantly reduced CHD risk, findings which agree with those from prior investigations.
The authors then extended their analysis by investigating 168 genetic variants associated with either LDL-C or TG modification. In order to make an “apples to apples” comparison, the associations were standardized to a 10 mg/dL difference in genetically-induced LDL-C reduction and a 50 mg/dL reduction in TG, which is equivalent to a 10 mg/dL reduction in VLDL-C (TG/5 = VLDL-C). Each 10 mg/dL reduction in LDL-C was associated with 15.4% lower odds for CHD (odds ratio = 0.846) and each 10 mg/dL reduction in VLDL-C (50 mg/dL reduction in TG) was associated with 18.5% lower odds for CHD (odds ratio = 0.815).
Since LDL and VLDL particles each contain Apo B, the authors also investigated the effects of a 10 mg/dL genetically-induced reduction in Apo B. The resulting odds ratio was 0.770, indicating 23% lower odds for CHD. When 10 mg/dL reductions in all three (LDL-C, VLDL-C and Apo B) were included in the same model, only Apo B remained significant (odds ratio = 0.761).
Comment on clinical implications. The Apo B concentration represents the total number of circulating particles with atherogenic potential. Most investigations have shown that Apo B predicts CHD risk slightly better than non-HDL-C, which is, in turn, a better predictor than LDL-C. The present study extends those findings by showing that genetic modification of Apo B concentration is strongly associated with CHD risk, supporting a causal relationship. The non-HDL-C concentration correlates strongly with the Apo B level because it represents cholesterol carried by the two main types of Apo B-containing lipoproteins, LDL and VLDL.
The National Lipid Association’s Recommendations for Patient-centered Management of Dyslipidemia identified non-HDL-C and LDL-C as co-primary targets of therapy for lipid modification (Jacobson 2014). The recent American Heart Association/American College of Cardiology Guideline on the Management of Blood Cholesterol (Grundy 2018) also acknowledges the importance of non-HDL-C by identifying thresholds for either LDL-C or non-HDL-C for consideration of adding adjunctive therapy to a statin as a way of identifying patients who could potentially benefit from additional Apo B-containing lipoprotein reduction. The results from this new study by Ference and colleagues suggest that a 10 mg/dL decline in VLDL-C has similar predictive value to that of a 10 mg/dL decline in LDL-C and that the predictive value of each is contained within the Apo B concentration.
In the US, Apo B measurement is not commonly completed. Since non-HDL-C correlates strongly with the Apo B concentration, it can serve as a reasonable surrogate. The National Lipid Association recommendations suggest goals for LDL-C of <70 mg/dL for those at very high risk and <100 mg/dL for others (Jacobson 2014). The corresponding goals for non-HDL-C are <100 and <130 mg/dL, respectively. It should be emphasized that the relationships show no evidence of thresholds, so reductions to levels of LDL-C and non-HDL-C well below 70 and 100 mg/dL, respectively, may be justified for some of the highest risk patients. Such an approach is supported by results from studies of adjunctive therapies, including those with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and ezetimibe.
Another important point with clinical relevance is that the reduction in CHD (or cardiovascular disease) risk with genetic variants is consistently larger than that observed in clinical trials of lipid-altering therapies. For example, in a Cholesterol Treatment Trialists’ Collaboration analysis (2010), each mmol/L (38.7 mg/dL) reduction in LDL-C was associated with a 24% reduction in major CHD event risk, which means that a 10 mg/dL reduction induced by statin therapy would reduce CHD event risk by 6.8% (1 – 0.76(10/38.7) = 0.068 or 6.8%), considerably less than the 15.4% lower odds for CHD in the Ference investigation. This likely reflects the greater length of time that individuals with genetic variants are exposed to altered levels of lipoproteins. The implication is that even modestly lower levels of LDL-C and VLDL-C can have important impacts on CHD risk if maintained over an extended period, which highlights the importance of healthy diet and adequate physical activity.
The recently published results from the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT) with eicosapentaenoic acid (EPA) ethyl esters showed an impressive reduction of 25% for major adverse cardiovascular events in patients with low baseline LDL-C (median 74 mg/dL) and elevated TG (median 216 mg/dL) (Bhatt 2019). The placebo-corrected reductions in non-HDL-C and Apo B in the active treatment group were 10 mg/dL and 5-8 mg/dL, respectively. The cardiovascular disease benefit was much larger than would be predicted based on the observed effects on non-HDL-C and Apo B over a period of ~5 years. Similarly, studies of other TG-lowering drug therapies such as fibrates have shown substantial reductions in risk among subsets of patients with elevated TG, especially if accompanied by low HDL-C (Sacks 2010, Maki 2016). In a meta-analysis completed by our group, cardiovascular disease risk reductions were 18% and 29% in studies of TG-lowering therapies in subgroups with elevated TG and elevated TG plus low HDL-C, respectively (Maki 2016). It appears unlikely that these results can be explained entirely by changes in non-HDL-C or Apo B levels. Therefore, additional research is needed to investigate pathways through which TG-lowering therapies affect cardiovascular risk.
In summary, genetically-induced reduction in LDL-C and VLDL-C (estimated as TG/5) are each associated with similar reductions in CHD risk. The predictive value of each of these is contained within Apo B. Since Apo B concentration is rarely measured in the US, non-HDL-C can serve as a surrogate marker and is a preferable target of therapy to LDL-C, because changes in both components of non-HDL-C (LDL-C and VLDL-C) appear to contribute similarly to risk alteration when compared on an “apples to apples” basis. Thus, a 50 mg/dL reduction in TG (equivalent to a 10 mg/dL reduction in VLDL-C) should be expected to produce the same benefit for CHD risk as a 10 mg/dL lowering of LDL-C.
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