Combined Lower LDL and SBP and Lifetime Risk of CVD

Study Questions:

What is the potential impact and association between lifetime exposure to the combination of both lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the lifetime risk of cardiovascular disease (CVD)?


Among more than 400,000 participants enrolled in the UK Biobank between 2006 and 2010 and followed through 2018, genetic LDL-C and SBP scores were used as instruments to randomly divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and CVD event rates between the groups were compared to estimate associations with lifetime risk of CVD. Main outcomes were odds ratio (OR) for major coronary disease events (MCE) including myocardial infarction, coronary deaths, and coronary revascularization.


The mean age of 438,952 participants was 65.2 years (range 40-80 years) and 54.1% were females. Compared to the reference group, participants with LDL-C genetic scores above the median had 14.7 mg/dl lower LDL-C and an OR of 0.73 for MCE (p < 0.001); participants with SBP genetic scores above the median had 2.9 mm Hg lower SBP and an OR of 0.82 for MCE (p < 0.001); and participants in the group with both genetic scores above the median had 13.9 mg/dl lower LDL-C, 3.1 mm Hg lower SBP, and an OR of 0.61 for MCE (p < 0.001). In a 4 x 4 factorial analysis, exposure to increasing combinations of lower LDL-C and SBP was associated with dose-dependent lower risks of MCE. In a meta-regression analysis, combined exposure to 1 mmol/L (about 40 mg/dl) lower LDL-C and 10 mm Hg lower SBP was associated with a 78% lower lifetime risk of CV events (OR, 0.22; 95% confidence interval [CI], 0.21-0.24; p = 1.8 x 10-139) and a 68% lower lifetime risk of CV death (OR, 0.32; 95% CI, 0.25-0.40; p = 6.9 x 10-12).


Combined exposure to both lower LDL and lower SBP was associated with independent, additive, dose-dependent reductions in the risk of CVD that increased over time. Therefore, most CV events can potentially be prevented with sustained exposure to combinations of modestly lower LDL and SBP.


Mendelian randomization analysis is a wonderful tool to assess the implications of plasma analyte and biometric risk factors that would need long-term randomized controlled trials in young to middle-aged persons to answer the questions addressed in this elegant study. The genetic scores were derived from 100 exome variants for LDL-C and 61 for SBP. That there is nearly a 40% reduction in major coronary events with the modest 14 mg/dl lower LDL-C and 3 mm Hg lower SBP compared to the reference group strongly supports the cost/benefit and importance of beginning to screen for elevated LDL-C and SBP in young persons, and provide opportunities for diet and exercise for primordial prevention throughout the world.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Nonstatins, Interventions and Coronary Artery Disease

Keywords: Blood Pressure, Cholesterol, LDL, Coronary Artery Disease, Exome, Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Risk Factors, Systole, ESC Congress, ESC 19

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