Lifelong Exposure to Lower LDL and BP Linked With Big Reduction in CVD Events

PARIS, France—Genetic predisposition to lower LDL cholesterol and systolic blood pressure levels over the course of a lifetime are associated with a lower risk of cardiovascular disease, new research shows. Importantly, even relatively small reductions in these two risk factors yields a significant boost in terms of cardiovascular disease prevention.

For example, a reduction in LDL cholesterol as low as 15 mg/dL combined with a 5-mm Hg reduction in systolic blood pressure was associated with a halving of the lifetime risk of cardiovascular disease. Scaled up, for each 38.67-mg/dL (1-mmol/L) reduction in LDL cholesterol combined with a 10-mm Hg reduction in systolic blood pressure, the lifetime risk of cardiovascular disease was reduced by nearly 80%.

“These data confirm that most cardiovascular events are preventable and suggest that most cardiovascular events can be prevented with prolonged exposures to combinations that modestly lower LDL cholesterol and systolic blood pressure,” said lead investigator Brian Ference, MD (University of Cambridge, England). “Secondly, because the benefits of low LDL cholesterol and systolic blood pressure increase over time, any combination, even small differences in lifetime exposure to both LDL and systolic blood pressure, can potentially result in dramatic lifetime reductions in the risk of cardiovascular disease.”

The results, which were presented during a Hot Line session at the European Society of Cardiology (ESC) Congress 2019, also strongly support the new ESC guidelines for the management of dyslipidemias that focus on a lifetime approach to cardiovascular risk reduction and lifestyle interventions to achieve lower LDL cholesterol goals at all risk levels.

Speaking with the media, Ference noted that a 15-mg/dL reduction in LDL cholesterol and a 5-mm Hg reduction in systolic blood pressure can be achieved with the DASH or similar diets. “These data are agnostic to the methods [by] which LDL cholesterol or systolic blood pressure are reduced,” he told TCTMD. “By whatever mechanism an individual can most effectively lower their LDL cholesterol and blood pressure—that’s the best way for that person if they can maintain it over time.”

UK Biobank Data  

Numerous trials to date have shown the cardiovascular benefits of lowering LDL cholesterol and systolic blood pressure, and mendelian randomization studies have suggested the clinical benefit of lower levels increases over time. The purpose of the present study, said Ference, was to quantify the effect of prolonged exposure to both lower LDL cholesterol and low systolic blood pressure on cardiovascular risk given that a long-term randomized, controlled trial would take decades to complete, is impractical, and is unlikely to occur.

The genetic analysis included 438,952 participants enrolled in the UK Biobank study. The researchers constructed a genetic LDL cholesterol score using 100 exome variants previously identified and linked with LDL cholesterol levels. They also constructed a genetic systolic blood pressure (SBP) score using 61 exome variants linked with systolic blood pressure.

Individuals were “naturally randomized” into four groups based on their genetic “lifetime exposure” to LDL cholesterol levels and systolic blood pressure:

• SBP and LDL cholesterol genetic risk scores ≤ median; mean LDL 144.5 mg/dL and mean SBP 139.2 mm Hg (n = 113,300)
• SBP risk score > median, LDL cholesterol risk score ≤ median; mean LDL 146.3 mg/dL and mean SBP 136.3 mm Hg (n = 111,097)
• LDL cholesterol risk score > median, systolic blood pressure risk score ≤ median; mean LDL 129.9 mg/dL and mean SBP 139.2 mm Hg (n = 109,027)
• LDL cholesterol and SBP risk scores > median; mean LDL 130.6 mg/dL and mean SBP 136.2 mm Hg (n = 105,528)

Individuals with an LDL genetic risk score higher than the median had LDL cholesterol levels 15.1 mg/dL lower—and a 26% lower risk of major coronary events—compared with individuals with LDL levels equal to or higher than the median. When scaled to 38.67 mg/dL (1 mmol/L), this translated into a 54% lower risk of major coronary events. Those with SBP risk scores higher than the median had blood pressure levels 2.9 mm Hg lower—and a 17% lower risk of coronary events—than those with an SBP risk score equal to or higher than the median. Scaled to 10-mm Hg lower systolic blood pressure, this translated into a 45% lower risk of major coronary events.

When combined, the benefits were additive. Those with LDL cholesterol and SBP risk scores higher than the median had a 39% lower risk of major coronary events. When scaled to a 38.67-mg/dL reduction in LDL cholesterol and a 10-mm Hg reduction in systolic blood pressure, major coronary events were lowered by 78%. Additionally, major cardiovascular events were lowered by 73%, nonfatal MI by 75%, ischemic stroke by 49%, and coronary death by 68%.

Frank Ruschitzka, MD (University Hospital, Zürich, Switzerland), who chaired the morning press conference, said the study results are not particularly surprising, but the genetic analysis reinforces the importance of primary prevention for reducing the lifetime risk of cardiovascular disease. Even small improvements in cardiovascular risk factors can have a significant impact given that the benefits accrue over time.

“The exposure over time [to elevated LDL and systolic blood pressure] has a huge impact,” he said. “Our studies don’t address that. They’re usually 5 or 7 years, but a study over 20 or 30 years isn’t doable. Yet we ask our patients when we diagnose them at 40 years old to take [a medication] for the next 40 or 50 years.” Even just a 10-mm Hg reduction in systolic blood pressure can have a massive impact, he said. “If a patient develops hypertension around 35 or 40 years, that’s 1.5 billion heartbeats against high blood pressure.”

Jemma Hopewell, PhD (University of Oxford, England), the scheduled discussant following the late-breaking presentation, said that randomized clinical trials testing various lipid-lowering strategies have shown that each 1-mmol/L reduction in LDL cholesterol lowers cardiovascular risk by 20% to 25%. Medium-term observational studies have shown the risk is lowered by approximately 30%. Longer-term mendelian randomization studies, on the other hand, have shown that risk is lowered by approximately 55% for each 1-mmol/L reduction in LDL cholesterol. Similar observations are observed in blood pressure.

While the present study underscores the importance of lower LDL cholesterol and blood pressures over the lifetime, Hopewell pointed out that the estimates in this paper relate to genetic predisposition to these risk factors. As such, estimating event reduction due to long-term medication use might not be entirely accurate, she said.