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Most cardiovascular (CV) events are preventable with sustained combinations of lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP).
Professor Brian Ference (University of Cambridge, Cambridge, UK) delivered this message yesterday in a Hot Line presentation of results from the UK Biobank study, which was published simultaneously in the Journal of the American Medical Assocation.1
“Randomised trials and Mendelian randomisation genetic studies have shown that the benefits of reducing LDL-C and reducing SBP accumulate over time. It seemed likely, therefore, that long-term combined reductions in both LDL-C and SBP could reduce the lifetime risk of CV disease (CVD),” says Prof. Ference. Given the number of patients involved and the projected timescale required—several decades—conducting a randomised trial to investigate this hypothesis is just not feasible. To fill this evidence gap, Prof. Ference explains, the team used genetic variants associated with lower LDL-C and lower SBP as instruments of randomisation.
More than 400,000 participants enrolled in the UK Biobank were included in the study. Patients were initially randomised into higher and lower plasma LDL-C groups, based on a 100-exome variant score, and then further randomised into higher or lower SBP groups, according to a 61-exome variant SBP score. The primary endpoint was the incidence of major coronary events defined as the first occurrence of a non-fatal myocardial infarction, coronary revascularisation or coronary death. There were no differences in baseline characteristics between the resulting four randomised groups: a reference group, a group with lower LDL-C, a group with lower SBP and a group with combined lower LDL-C and lower SBP.
Compared with the reference group, the lower LDL-C group had a 14.7 mg/dL lower LDL-C and a 27.0% lower risk of major CV events (odds ratio [OR] 0.73), while the lower SBP group had a 2.9 mmHg lower SBP and an 18% lower risk (OR 0.82). Importantly, the group with both lower LDL-C and SBP had both 14.7 mg/dL lower LDL-C and 3.1 mmHg lower SBP, and a 39% lower risk of major CV events (OR 0.61). Of note, the effects of lower LDL-C and lower SBP on the risk of CV events were independent, additive and dose-dependent. Any combination of lower LDL-C and lower SBP was associated with a correspondingly lower lifetime risk of CVD.
With greater reductions of 1 mmol/L (38.7 mg/dL) lower LDL-C and 10 mmHg lower SBP, there was an 80% lower lifetime risk of CVD and a 68% lower risk of CV death.“Because benefits accumulate over time,” says Prof. Ference, “even small differences in LDL-C and SBP can lead to large reductions in the lifetime risk of CVD, if the reductions are maintained long term.” He thinks this has important implications for the impact of lifestyle changes. “These modest changes in LDL-C and SBP are in the range of those you might expect to see with prescribed diets, such as the Dietary Approaches to Stop Hypertension (DASH) diet. Not only do the results underline the importance of lifestyle changes, they also suggest that recommendations for such changes can be substantially simplified to focus on the common goal of achieving and maintaining a combination of reduced lipids and blood pressure.” The optimal regimen should be tailored to the individual. “There is no universal ‘best’ regimen to follow. Instead, the ‘best’ modification for any individual is the one that leads to the greatest LDL-C and SBP reductions for that person. Crucially, this regimen should also be one that the individual can adhere to long-term.”
Prof. Ference concludes, “To prevent avoidable CV events, we need to encourage patients to minimise their risk by adopting healthy lifestyle choices early in their life and then sustaining them over time. If larger reductions in LDL-C and SBP are required to reduce lifetime risk, early initiation of medication can be considered—further research is required to identify who would benefit most from early treatment.”
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