Key clinical point: Individuals with genetic predisposition to low LDL cholesterol and low systolic blood pressure had lifetime risk of cardiovascular disease that was 80% less than that of a reference population.
Major finding: Reduction in LDL cholesterol of 1 mmol/L and SBP of 10 mm Hg was tied to a lifetime 80% reduction in CVD risk.
Study details: Mendelian randomization trial of 438,952 participants in the UK Biobank study.
Disclosures: The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation. 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.
Ference B. et al. ESC Congress 2019, Hot Line Session 3.
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.