Positive Correlation Found Between Combined Life-time Exposure of Decreased LDL-C and Low Systolic BP in Lowering the Risk of Cardiovascular Disease Mendelian randomization analyses involving approximately half a million participants reveals the association of lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure with lower cardiovascular risk

Sara Mohsin, MD
By Sara Mohsin, MD on

A recent study by Brian A. Ference et al. based on a UK Biobank study, published in JAMA, has shown that life-time exposure to decreased low-density lipoprotein cholesterol (LDL-C) levels and low systolic blood pressure (SBP) leads to a decreased lifetime risk of cardiovascular disease. Nonetheless, these findings do not constitute the quantified benefit of treating these risk factors in decreasing the life-time cardiovascular disease risk.

This randomized study included the data from 438, 952 individuals who were the participants of the UK Biobank study with the mean age of 65.2 years (range: 40.4 – 80.0 years) and 54.1% female participants. Participants were divided into a total of 4 groups, and 4 x 4 factorial reasoning was carried out. First participants were divided into 2 groups based on having a genetic LDL-C score being equal to or lower than, or higher than the median value. Second, they were further subdivided into 2 groups based on having their genetic systolic BP score being equal to, or lower than, or higher than the median value. The reference group further included 3 groups with each individual group having a higher LDL-C genetic score than the median, higher SBP scores than the median, and combined LDL-C and SBP genetic scores higher than the median, respectively. Differences in the plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to evaluate the correlations with the lifetime cardiovascular disease risk. The primary outcome included major coronary events which were characterized as a composite of coronary death, coronary revascularization, or nonfatal myocardial infarction. The key secondary outcomes were major cardiovascular events defined as the occurrence of a major coronary event or ischemic stroke.

When compared with the reference group, participants having LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels with an Odds ratio of 0.73 for major coronary events (95%CI: 0.70 – 0.75; P < 0.001). Participants with SBP genetic scores higher than the median had 2.9 mmHg lower SBP with an Odds ratio of 0.82 for major coronary events (95%CI: 0.79 – 0.85; P < 0.001). Finally, the participants in the group with both genetic scores higher than the median had 13.9 mg/dL lower LDL-C, 3.1 mmHg lower SBP, with an Odds ratio of 0.61 for major coronary events (95%CI: 0.59 – 0.64; P < 0.001). In a 4×4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67 mg/dL lower LDL-C and 10 mmHg lower SBP was associated with an Odds ratio of 0.22 for major coronary events (95%CI: 0.17 – 0.26; P < 0.001), and 0.32 for cardiovascular death (95%CI: 0.25 – 0.40; P < 0.001). These findings concluded the positive correlation of lifelong genetic exposure to lower LDL-C levels and lower SBP with the overall lower cardiovascular disease risk without any regard to the magnitude of benefit achieved after treating these risk factors.

There are several limitations to this study, including the lack of evaluation of risks and benefits of medications associated with lowering the LDL-C and SBP. Second, there is a lack of evidence proving that outcomes associated with naturally occurring lower LDL-C or SBP levels are the same as the outcomes associated with extrinsic drug treatment or other interventions to achieve similar plasma LDL-C or SBP levels. Hence, these study findings fail to quantify the amount of benefit gained from various treatments to lower LDL-C, SBP, or both.

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