Natural randomization study shows that lifelong modestly lower LDL-c and SBP greatly reduces CV risk
Combined effect of lower LDL-c and lower SBP on the lifetime risk of cardiovascular disease
Presented at ESC Congress 2019 in Paris, France by Brian A Ference (Cambridge, United Kingdom)
Introduction and methods
Numerous randomized trials have demonstrated that lowering LDL-c and SBP each reduces the risk of CV events. In addition, Mendelian randomization studies suggest that the clinical benefit of lower LDL-c and SBP may increase over time. Together, these studies suggest that long-term exposure to the combination of both lower LDL-c and lower SBP could potentially substantially reduce the lifetime risk of CV disease. However, the effect of prolonged exposure to both lower LDL and lower SBP on the risk of CV disease has not been reliably quantified.
This analysis therefore aimed to quantify the association between long-term exposure to the combination of both lower LDL-c and lower SBP on the lifetime risk of ASCVD.
Because it is not feasible to conduct a randomized trial to answer this question, this study used genetic variants associated with lower LDL-c and lower SBP to ‘naturally randomize’ participants to lifetime exposure to lower LDL-c, lower SBP, or both. This ‘naturally randomised trial’ approach can be considered analogous to a long-term RCT.
Data were used of 438,952 participants enrolled in the UK Biobank. An LDL-c genetic score based on 100 exome variants was used, and participants were divided into LDL-c score greater than vs equal or below the median. Similarly, an SBP genetic score based on 61 exome variants was used to further divide the groups (greater than vs. equal or below the median), yielding four groups. The primary outcome was major coronary events (non-fatal MI, coronary revascularization or coronary death, n=24,980).
- The difference in LDL-c level between the genetic score based groups was 15.1 mg/dL. Among those with LDL-c score ≤median, the difference in SBP was 2.3 mmHg, and in those with LDL-c score >median, the difference in SBP was 3.0 mmHg.
- The combined effect of lower LDL-c and SBP lowered the risk of the primary outcome by 39% in this study (OR: 0.61, 95%CI: 0.59-0.64). Standardized to 1 mmol/L lower LDL-c and 10 mmHg lower SBP, this amounts to an OR of 0.22 (95%CI: 0.21-0.24).
- The combined effect also lowered the key secondary outcome of major CV events (OR: 0.65, 95%CI: 0.63-0.68). Standardized, this yields an OR of 0.27 (95%CI: 0.25-0.29).
- Several secondary outcomes showed similar risk reductions, including coronary death (OR: 0.69, 95%CI: 0.62-0.77, standardized: OR: 0.32, 95%CI: 0.25-0.40).
- Plotting the proportional risk reduction on a log-odds scale with all combinations of LDL-c and SBP score groups, showed that any combination of lifelong lower LDL-c & SBP is associated with a dose-dependent lower lifetime risk of CV disease that is log-linearly proportional to the absolute combined difference in LDL-C and SBP
Lifetime exposure to lower LDL-c and lower SBP have independent, additive, and dose-dependent effects on the lifetime risk of CV disease. The data suggest that most CV events may be prevented with prolonged exposure to the combination of both lower LDL-c and SBP. Lifetime exposure to the combination of 1 mmol/L (38.67 mg/dL) lower LDL-c and 10 mmHg lower SBP was associated with an 80% lower lifetime risk of CV disease and a 68% lower lifetime risk of CV death. The large proportional reductions in risk associated relatively small differences in lifetime exposure to LDL-c and SBP in this study suggest that the effect of LDL-c, SBP and combined exposure to both on the risk of CV disease is determined by both the magnitude and duration of exposure. It is therefore important that the exposure to lower levels is sustained over time.
In a brief discussion during the press conference, prof Ference was asked how he uses this information in discussions with this patients. He noted that benefit is a better motivator than risk. By estimating how they can benefit from improving risk factors, he can encourage them to remain compliant and to invest in their health over the long term.
- Our reporting is based on the information provided at the ESC congress -