Long-term Exposure to Lower LDL Cholesterol, Blood Pressure Has Potential to Dramatically Cut CV Risk

ROME, Italy—Individuals predisposed to low levels of both LDL cholesterol and systolic blood pressure have greater reductions in cardiovascular disease over the course of decades than those with low levels of either factor individually, a mendelian randomization study shows.

In fact, combined exposure to LDL cholesterol levels that were 1 mmol/L lower and systolic blood pressure that was 10 mm Hg lower yielded an 86.1% relative reduction in the risk major vascular events (OR 0.139; 95% CI 0.114-0.170) during follow-up of 32 years, Brian Ference, MD (Wayne State University, Detroit, MI), reported here at the European Society of Cardiology Congress 2016.

That represents the maximum potential benefit an individual can achieve over the long term, he added, with lesser reductions in cholesterol and blood pressure and shorter durations of exposure providing less substantial reductions.

“Our study confirms that cardiovascular events are largely preventable, and it suggests that the prevention of cardiovascular disease can be substantially improved and simplified by designing prevention strategies that focus on promoting long-term exposure to lower LDL and lower blood pressure beginning in early adulthood,” Ference said at a press conference.

But Richard Becker, MD (University of Cincinnati Heart, Lung & Vascular Institute, OH), who was not involved in the study, told TCTMD that efforts could begin even earlier, perhaps in schools.

Showing that maintaining low levels of LDL cholesterol and blood pressure over the long term has the potential for such dramatic benefits creates challenges for patient management, “but I would also say that it creates opportunities in terms of how we manage risk factor modification at a population health level,” said Becker, a spokesperson for the American Heart Association.

“It means that we need to start screening blood pressure and lipids probably in the first 10 years of life,” he said, pointing to pediatric literature showing that some children and teens already manifest signs of high blood pressure and cholesterol.

“In the United States and now worldwide our entire paradigm for identifying risk has to move much further upstream, and there has to be some concerted effort at the population health level to be able to control it,” he continued. “If we use a downstream approach where people have already started having events and we work backward from there instead of using a proactive preventive approach, we’re going to miss the bigger picture.”

Reconciling With HOPE-3

Ference and colleagues used genetic information on 102,773 participants of 14 prospective cohort or case-control studies to form groups of patients with low LDL cholesterol levels, low systolic blood pressure, or both by using a 2x2 factorial mendelian randomization design.

During more than 3 decades of follow-up, there were 14,368 major vascular events, including coronary heart disease death, MI, stroke, or coronary revascularization.

The “independent, multiplicative, and cumulative causal effects” of lower LDL cholesterol and systolic blood pressure on cardiovascular risk were consistent across multiple cardiovascular endpoints, Ference reported. Noncardiovascular death was unaffected, but a relative 84% reduction in coronary heart disease death resulted in a 36% relative reduction in all-cause mortality.

The findings were also consistent across subgroups defined by sex, smoking status, diabetes status, and levels of LDL cholesterol and systolic blood pressure, “suggesting that the benefit of combined exposure to lower LDL and lower systolic blood pressure would extend to persons who have apparently normal blood pressure and cholesterol levels,” Ference said.

At first glance, the results appear to conflict with those from the HOPE-3 trial reported in April. That study showed that reducing LDL cholesterol with a low-dose statin and blood pressure with an angiotensin receptor blocker and thiazide diuretic prevented cardiovascular events in intermediate-risk patients without cardiovascular disease, but that the effect—a 29% relative reduction—was largely due to the lipid-lowering effects with no significant contribution from dropping blood pressure.

There was only a nonsignificant reduction in events from lowering blood pressure in HOPE-3, Ference noted, but when that effect is multiplied by the 25% reduction in events with lipid-lowering it equals the overall impact of the combined interventions.

“So we would suggest that our data are perfectly consistent with the HOPE trial,” Ference said. “It’s just that the magnitude of the blood pressure-lowering may not have been large enough and the follow-up may not have been long enough in order to translate into a statistically significant effect.”

‘Big Data’ Informs Public Health Strategies

Ference said the current analysis “focuses the emphasis on monitoring and maintaining lower blood pressure and cholesterol beginning much earlier than is currently recommended,” which can help guide emerging countries coping with an “explosion of risk factors” in implementing public health policies.

“As we enter into the era of biometric monitoring and big data . . . we can use that data to choose those components of the diet or activities or lifestyle factors that maintain our blood pressure and cholesterol as low as possible for as long as possible as a strategy to reduce our lifetime risk of cardiovascular disease,” he said.

Depending on the population, the large-scale public health interventions needed to address these issues could take the form of screening in schools or using polypills in areas with poor access to healthcare, Becker said.

“When you’re talking about tens of millions of people you have to look for something that really has the ability to reach large numbers,” he said, adding, however, that “it’s a work in progress.”

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Ference BA, Ference TB, Brook RD, et al. A naturally randomized trial comparing the effect of long-term exposure to lower LDL-C, lower SBP, or both on the risk of cardiovascular disease. Presented at: European Society of Cardiology Congress 2016. August 29, 2016. Rome, Italy.

  • Ference reports receiving research contracts from Merck Sharp & Dohme, Amgen, and Esperion Therapeutics and having other relationships with Merck Sharp & Dohme, Esperion Therapeutics, Celera, and Ionis Pharmaceuticals.
  • Becker reports no relevant conflicts of interest.