Cumulative Burden of LDL Cholesterol Increases CHD Risk

Increasing exposure to LDL cholesterol in young adulthood and middle age is associated with a significantly increased risk of coronary heart disease (CHD) independent of midlife lipid levels, according to the results of a new analysis.

The findings, published online September 22, 2021, in JAMA Cardiology, emphasize the importance of maintaining an optimal LDL cholesterol level starting early in life, say researchers.

Equally important, the findings suggest “that clinical decisions for managing patient risk might be best guided by serial LDL cholesterol measurements and cumulative LDL cholesterol burden, as opposed to contemporary lipid values,” lead investigator Yiyi Zhang, PhD (Columbia University Irving Medical Center, New York, NY), told TCTMD. “Current clinical practice usually focuses on LDL cholesterol in middle age and bases treatment decisions on a single measurement. It might be time to incorporate serial measurements, or the cumulative burden of LDL cholesterol, into clinical decision-making.”

In an editor’s note accompanying the analysis, Ann Marie Navar, MD, PhD (UT Southwestern Medical Center, Dallas, TX), and Gregg Fonarow, MD (University of California, Los Angeles), point out that several observational studies have now shown that exposure to LDL cholesterol increases CVD risk in a “dynamic and cumulative fashion, similar to pack-years in smoking.” For this reason, they suggest that earlier treatment, similar to how high blood pressure is managed, be considered for elevated LDL cholesterol levels.  

“As of now, those with elevated LDL are only recommended for treatment if they have extremely high LDL cholesterol or other risk factors,” Navar told TCTMD. “This is despite our knowledge that leaving LDL cholesterol untreated even if it’s mildly elevated—for example, over 100 mg/dL—early in life allows potentially decades of exposure to atherogenic lipoproteins. If someone’s blood pressure is 150 mm Hg we don’t tell the patient, ‘You don’t have other risk factors and your 10-year risk is low, so we can leave this alone.’ And [yet] blood pressure medications arguably have as many if not more side effects than statins.”

Cumulative Burden of LDL Cholesterol

The researchers pooled data from four prospective cohort studies with repeated LDL cholesterol measurements—ARIC, CARDIA, the Framingham Heart Study Offspring Cohort, and MESA—to evaluate how cumulative exposure to LDL cholesterol, time-weighted average (TWA)-LDL cholesterol, and the change in the LDL cholesterol “slope” from young adulthood to middle age were associated with incident CVD. Cumulative exposure was calculated as the LDL cholesterol value multiplied by years exposed while the TWA was defined as the cumulative exposure divided by the duration of exposure. The slope of the LDL curve from one measurement to the next reflects the change in lipid values over time, with a steeper slope representing a rapid increase in LDL levels.

From the four studies, 18,288 participants (mean age 56.4 years; 56.4% women) were included in the analysis. The study was restricted to people who had two or more LDL cholesterol measurements taken at least 2 years apart between the ages of 18 and 60 years, with at least a single measurement occurring in middle age (40 to 60 years). Overall, the mean LDL level at the time of the index visit was 123.0 mg/dL, the cumulative LDL level was 4,837 [mg/dL x years], and TWA-LDL level was 125.6 mg/dL. The slope of the LDL cholesterol curve was 0.7 mg/dL/year.

On multivariable analysis, those with the greatest cumulative exposure and highest TWA-LDL cholesterol levels—those in the highest quartile—had a higher risk of CHD compared with those with less cumulative exposure and lower TWA-LDL levels. There was no significant association between the slope of change in LDL cholesterol levels, nor was there any significant association between LDL cholesterol and incidence of stroke or heart failure no matter how LDL cholesterol was measured.

Association of Cumulative LDL Cholesterol with Incident CHD

Association of TWA-LDL Cholesterol with Incident CHD

In terms of why there was no association with the change in LDL cholesterol (slope), Zhang said it’s possible that those with a steeper slope between the two measurements might reflect a smaller lifetime burden. “If you think of two people with the same LDL cholesterol at middle age, those who arrive at a level with a steeper slope might actually have a smaller cumulative LDL level, or a smaller area under the curve,” she said.

‘Reverse Disease Course and Prevent Future CHD’

Zhang said the best way to maintain optimal LDL cholesterol levels throughout the life span is with a healthy diet and physical activity, but it’s possible this might not be enough in some people. Treatment usually starts later in life, after middle age, so there are some arguments about whether it should begin earlier “as opposed to waiting until they already develop atherosclerosis,” she said.

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for primary prevention recommend lipid testing in adults starting at age 20 while the United States Preventive Services Task Force recommends checking once men and women are 35 and 45 years old, respectively.

Navar, who published an analysis in 2015 showing that hyperlipidemia in early adulthood increases the lifetime risk of CHD, said that she follows the ACC/AHA screening recommendations because it’s important to identify those with severely elevated LDL cholesterol and possible familial hypercholesterolemia, a lipid disorder that is known to be underdiagnosed. In addition, early lipid screening can help promote lifestyle changes that are necessary in some patients. Despite the early screening, Navar believes the current clinical guidelines are missing a “huge opportunity” to lower CVD risk by undertreating high LDL cholesterol levels in young people.

“Personally, I often recommend statins for people with elevated LDL cholesterol early in life to lower their lifetime risk,” she said. “They are safe, well tolerated, and affordable.”