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Low LDL-C and blood pressure can reduce lifetime CVD risk by 80%

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Mendelian randomization studies show striking effects of a lifetime of low lipids, blood pressure

Jemma Hopewell, PhD, was the assigned discussant for the Mendelian randomization study of LDL-C and SBP’s effects on cardiovascular health. She placed the genetic epidemiological study within the framework of other short- and medium-term studies that have examined the effects of LDL-C and SBP on cardiovascular health.

“Let’s think about this in the context of other studies,” said Dr. Hopewell, asking what the study adds to what’s known about exposure to LDL-C and systolic blood pressure levels. Shorter-term clinical trials that tracked differences in LDL-C over about 5 years have shown a 20%-25% drop in cardiovascular risk, while medium-term observational studies have shown a decrease of about 30%.

Now, she said, Mendelian randomization studies such as this analysis of the UK Biobank data are showing larger effects with the lifelong exposure to lower LDL levels that genetic variants confer. “As you can see, a pattern emerges ... of larger effects on risk than might be anticipated from the short-term clinical trials.”

A similar pattern can be seen with SBP, with shorter-term clinical trials showing smaller reductions in CVD. Observational studies show more reduction in risk when participants are followed for longer periods, and studies such as the present one show the larger effects of a lifetime of lower blood pressure, said Dr. Hopewell.

In terms of the combined effects, “It’s for the first time today that we see these nice results in a Mendelian randomization framework. This is a very well conducted analysis.”

Still, she cited potential limitations that can inform interpretation of the study results. These include the fact that Biobank participants have been followed for just about 10 years at this point, with most participants still alive. “Therefore, it is unclear whether this truly reflects the lifetime risk of coronary events.”

Also, the paucity of ethnic variation in the Biobank cohort means generalization is problematic until studies are conducted across different ethnic groups, she said.

The study design leaves open the possibility for reverse causality given the fact that participant characteristics captured at the time of recruitment may be influenced by prior disease, said Dr. Hopewell.

She also cited the complication of pleiotropy that’s a known limitation of Mendelian randomization studies. Importantly, the study’s reliance on genetic variation means that results may not directly translate to long-term use of lipid-lowering medication and antihypertensives, she said.

Still, the effects seen with the Biobank population bolster the importance of prevention efforts. “This really is quite encouraging,” said Dr. Hopewell. “Small differences over a long period of time have a material impact on risk.”

Dr. Hopewell is associate professor and senior scientist in genetic epidemiology and clinical trials at Oxford Cardiovascular Science, University of Oxford, England. She disclosed research contracts from unspecified pharmaceutical companies, and she has a fellowship from the British Heart Foundation.



– Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

Illustration of gene mutation SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

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