Earlier, Longer Interventions Proposed for Optimal Population LDL Cholesterol

When it comes to strategies for lowering population-level LDL cholesterol, the healthcare community needs to start thinking about cumulative exposure as opposed to finding aggressive, short-term solutions, according to the authors of a new paper.

“This is a concept that says a small change, for example, maintained for a long period of time gives you the same benefit as a large change maintained for a short period of time, in terms of risk difference,” senior author Kausik Ray, MD (Imperial College London, England), told TCTMD. Ray co-authored the paper, published last week ahead of print in Circulation, with Julia Brandts, MD (University Hospital RWTH Aachen, Germany).

This paradigm allows you to more effectively tap into lifestyle, Ray continued. “If you were able to pick people at risk and identify them early enough and you were able to change their exposure, if you will, early and maintain it and lock that down for a 20-, 30-, 40-year time horizon, that in itself may be enough rather than waiting until later in life and then trying to use a sledgehammer.”

Ray and Brandts’ paper points to adherence as the biggest contemporary barrier to LDL-lowering, an issue that has not yet been solved by a variety of proposed patient-tailored and technological strategies. Additionally, the authors say the asymptomatic nature of CV risk factors is another “crucial barrier to long-term adherence.”

Ray said he was inspired to write this paper after seeing patients continue to develop problems despite all of the advancements in the field of prevention. “It's great if you can write a paper and you can do trials and you can do all of those things and you think, ‘Hey, that's really cool.’ But then when you treat patients and you see the gap between what we think of the . . . results of the trial and the implementation and the practicalities of daily life, [you see this] is a problem all around the world.” He asked: “How might we change this paradigm?”

Thinking bigger picture in terms of LDL reduction is not “necessarily rocket science, but nobody has ever tried to put it that way,” Ray explained. “I think it's helpful because what it does is it starts to help people think about population health. Because as we develop new tools, instead of just thinking about well it's just the individual, here we can think about things that might be scalable.”

A Shift in Thinking

The paper outlines the available evidence in an effort to “shift the way that we think about treating cholesterol,” according to Ray. Similar thought processes could be applied to both blood pressure and glucose control, he noted.

Ray and Brandts review the currently available medication options for LDL cholesterol-lowering—statins, monoclonal antibodies (mAbs), and small interfering RNAs (siRNAs). “If we assume that imperfect adherence at a population level causes suboptimal reductions in LDL cholesterol, then a theoretical 39 mg/dL reduction observed soon after initiation will not be sustained when the therapeutic time horizon is extended,” they write. “Differences in adherence to treatment regimens will differentially impact therapies which have different durations of action.”

For example, over 5 years the population level impact of each of the aforementioned approaches might produce less than the expected 22% lowering of risk expected per 39mg/dL LDL cholesterol, they say, calculating predicted proportional risk reductions of 13.5% for statins, 17.5% for mAbs, and 22% for siRNAs. “Projecting over a 50-year therapeutic window, the cumulative benefits of maintaining the same LDL cholesterol differences are even more marked at a population level, where one might expect a 31.2% relative risk reduction for statins, 41.6% for mAbs, and 52% for siRNAs,” they write.

The potential for infrequent interventions like vaccinations or even gene editing, though both still in development, may have an even greater long-term effect.

All of this gets at the ultimate goal of preventing rather than treating disease. “It suggests that if we move prevention much earlier along people's life course and you have convenient ways of doing this, then you might actually get the same return as using more potent treatments later on,” Ray said.

Of course, there are societal barriers to this way of thinking. Most people are only focused on short-term risk, he explained. “Everybody says, ‘Well, my risk in the next 5 years or 10 years is really low,’ and age is such a big determinant of that. When you move toward lifetime risk, then actually you might start to think about changes much, much earlier.”

While patients “tend to accept” earlier lifestyle modifications, “there are some people where lifestyle may not be enough to change the trajectory,” Ray continued. “So we need to then start thinking about medications, whether we like it or not.” The challenge moving forward for providers will be maintaining an adequate level of engagement with these patients over their lifetime as well as making it convenient for them to adhere to therapy.