Cholesterol lowering at younger age may be more rewarding, suggests JAMA study.

Guidelines dictate us to treat all hypertensives in young age without need for any risk stratification. Has the time come to adopt a similar approach in managing dyslipidemia in youngsters without resorting to 10 year risk score calculations? New findings from a study published in JAMA Cardiology suggests a paradigm shift in managing dyslipidemia in young age. Zhang et al have shown that cumulative LDL-C and time weighted average (TWA) LDL-C during young adulthood and middle age are associated with the risk of incident coronary heart disease (CHD), independent of midlife LDL-C level.

These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

When exactly to begin lipid-lowering therapy has not yet been well demarcated. Atherosclerotic lesions develop slowly over many years, if not decades. However, guidelines for lipid management have largely recommended statins on the basis of a 10-year risk of cardiovascular events rather than the risk of developing atherosclerosis over a lifespan. As a result, young adults (aged <40 years) are eligible for statins only if they have familial hyperlipidemia, severely elevated LDL-C level (>190 mg/dL; to convert to millimoles per liter, multiply by 0.0259) or LDL-C of 160 mg/dL or higher, and a family history of premature atherosclerotic cardiovascular disease.

Multiple observational studies have now demonstrated that exposure to LDL-C increases cardiovascular disease risk in a dynamic and cumulative fashion, similar to pack-years in smoking.

In the latest issue of JAMA Cardiology, Zhang et al analyzed the data of a large number of participants in 4 national cohort studies with the aim to evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.

Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. The study modeled LDL-C exposure starting at age 18 years to show granularly how risk from cumulative LDL-C exposure starts to accumulate early in life.

Increasing cumulative exposure to LDL-C (in mg/dL × years) was associated with increasing risk in a nearly linear fashion, independent of midlife lipid levels. When evaluated as time-weighted average LDL-C, risk began to increase at a mean LDL-C level of as low as 100 mg/dL, far below current treatment thresholds.

"Findings from the study by Zhang et al suggest that the current guideline-endorsed paradigm of deferring the treatment of mild and moderate elevations of LDL-C levels in young adults not only misses a critical opportunity for prevention but also unnecessarily allows lipid-related risk to accumulate for decades", note Navar et al in an accompanying editorial.

"We found that cumulative LDL-C and TWA LDL-C levels were associated with an increased risk of incident CHD events, even after adjusting for the most recent LDL-C level during middle age", add authors in discussion.

The results are supported by biological mechanics of lipid metabolism. Low-density lipoprotein cholesterol and other apolipoprotein B–containing lipoproteins that are smaller than 70 nm in diameter freely enter and exit the endothelial barrier, where they can interact with extracellular structures, such as proteoglycans, to become retained in the extracellular matrix. The LDL-C particles that are retained in the arterial wall are oxidized and then elicit an inflammatory response, which results in vascular injury and atheroma formation.

Therefore, an individual's total atherosclerotic burden is believed to be associated with both the circulating LDL-C levels and the total duration of exposure.

"Clinical decisions are currently guided by contemporary LDL-C values, whereas our findings suggest that incorporating serial LDL-C measures and cumulative LDL-C burden into clinical practice may further refine CVD risk assessment and help inform strategies for primary prevention of CHD", add authors.

Source: JAMA Cardiology:

1. doi:10.1001/jamacardio.2021.3508

2. doi:10.1001/jamacardio.2021.3517