Cumulative exposure to LDL-C from young to middle age linked to risk of CHD events, but not ischemic stroke or HF

Maintaining optimal low-density lipoprotein cholesterol (LDL-C)—even during young adulthood—may reduce the lifetime risk for atherosclerotic cardiovascular disease, according to results from a recent study published in JAMA Cardiology.

Risks of midlife coronary heart disease (CHD) events were associated with cumulative LDL-C and time-weighted average (TWA)-LDL-C during young adulthood and middle age, researchers found, and recommended a shift towards optimal LDL-C management earlier rather than later in life.

“It is important to maintain an optimal level of LDL-C throughout young and middle age to minimize the cumulative exposure to LDL-C to reduce the lifetime risk of developing atherosclerotic cardiovascular disease. Understanding young adult levels of LDL-C may help inform management decision-making in middle age,” lead author Yiyi Zhang, PhD, Columbia University Medical Center, New York City, told BreakingMED.

To assess the effects of long-term LDL-C exposure and its role in CVD risk, Zhang and colleagues pooled data from four prospective studies, including the Atherosclerosis Risk in Communities Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study Offspring Cohort, and the Multi-Ethnic Study of Atherosclerosis), and included 18,288 patients (mean age: 56.4 years; 56.4% women; 71.0% non-Hispanic White) who had two or more measurements of LDL-C taken between ages 40-60 years.

Primary outcomes included incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).

After a median follow-up of 16 years, they identified 1,165 CHD events, 599 ischemic strokes, and 1,145 HF events. Upon multivariate Cox proportional hazards regression modeling adjusted for demographic and clinical risk factors, hazard ratios (HRs) for CHD comparing top and bottom LDL-C variable quartiles were as follows:

  • Cumulative LDL-C level: 1.97 (95% CI, 1.50-2.58; P for trend<0.001).
  • TWA LDL-C level: 1.95 (95% CI: 1.54-2.46; P for trend<0.001).
  • LDL-C slope: 1.26 (95% CI: 1.03-1.55; P for trend=0.02).
  • LDL-C index visit levels: 1.79 (95% CI: 1.49-2.14; P for trend<0.001).

Upon multivariate Cox proportional hazards regression modeling adjusted for other CVD risk factors and the most recent LDL-C level, HRs for CHD were:

  • Cumulative LDL-C level: 1.57 (95% CI: 1.10-2.23; P for trend=0.01).
  • TWA LDL-C level: 1.69 (95% CI: 1.23-2.31; P for trend<0.001).
  • LDL-C slope: 0.88 (95% CI: 0.69-1.12; P for trend=0.28).

Zhang et al found no associations between ischemic stroke or HF for any LDL-C variables. All patterns of associations were similar in men and women, but associations between cumulative LDL-C and TWA LDL-C with CHD were stronger in non-Hispanic White patients compared with non-Hispanic Black patients.

In an accompanying editorial, Ann Marie Navar, MD, PhD, of the University of Texas Southwestern Medical Center, and Associate Editor, JAMA Cardiology, and Gregg C. Fonarow, MD, of Ahmanson-UCLA Cardiomyopathy Center, David Geffen School of Medicine, UCLA, and Section Editor, JAMA Cardiology, applaud these results from Zhang and colleagues, adding that they specifically highlight the need to revise current guidelines.

“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,” they wrote.

“Current hypertension guidelines recommend the treatment of all adults with elevated blood pressure regardless of risk because of the long-term risk of untreated hypertension, although the outcomes of trials for lowering blood pressure in young adults are also lacking. If the clinical community can support treating hypertension early in life to prevent the long-term risks of elevated blood pressure, the findings in the study by Zhang et al suggest that a similar paradigm should be considered for LDL-C,” Navar and Fonarow concluded.

Zhang concluded by stressing the potential of these results to effectively and significantly lower future cardiovascular risks.

“These findings have substantial clinical implications. Clinical decisions are currently guided by contemporary LDL-C values, whereas findings from this study suggest that incorporating serial LDL-C measures and cumulative LDL-C burden over years into clinical practice may further refine CVD risk assessment and help inform strategies for primary prevention,” Zhang told BreakingMED, and added that roughly 7% of young adults (18-40 years) in the U.S have LDL-C levels >160 mg/dL.

“Also, as the risk of developing atherosclerotic plaques and CHD events is determined by the cumulative exposure to LDL-C, it is plausible that achieving optimal lipid levels early in life and maintaining those optimal levels throughout adulthood may more effectively prevent CVD as opposed to the current paradigm of deferring LDL-C-lowering to later ages when atherosclerosis is likely already advanced,” she concluded.

Study limitations include the use of imputation to estimate long-term LDL-C exposures, and the low incidence of ischemic stroke events compared with incident CHD events.

  1. Cumulative LDL-C exposure during young adulthood and middle age was associated with the risk of incident coronary heart disease events, independent of midlife LDL-C level.

  2. Researchers found no associations between cumulative LDL-C and future incidence of ischemic stroke, heart failure.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by the National Institutes of Health.

Zhang reported no disclosures.

Navar reported receiving grants from Bristol Myers Squibb, Esperion, Amgen, and Janssen; receiving personal fees from Amarin, Amgen, Astra Zeneca, Boehringer Ingelheim, CSL, Esperion, Janssen, Lilly, Sanofi, Regeneron, NovoNordisk, Novartis, The Medicines Company, New Amsterdam, Cerner, 89Bio, and Pfizer outside the submitted work; and being the associate editor of JAMA Cardiology.

Fonarow reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis outside the submitted work, and being the section editor of JAMA Cardiology.

Cat ID: 4

Topic ID: 74,4,730,4,192,925