More evidence supports the link between low-density lipoprotein (LDL) cholesterol levels and an increased risk of intracerebral hemorrhage (ICH).

Results from a large, prospective longitudinal study show individuals with LDL below 70 mg/dL had a 65% increased likelihood of ICH over 9 years.

Furthermore, the participants with LDL below 50 mg/dL had 169% greater risk compared with their counterparts who had levels in the 70 to 99 mg/dL range.

"Consistently, previous population-based studies already reported that low LDL cholesterol level could be associated with high ICH risk. However, LDL cholesterol level was only assessed once in these studies — and it remains unclear whether long-term LDL status is associated with altered ICH risk," study investigator Xiang Gao, MD, PhD, associate professor and director of the Nutritional Epidemiology Lab at Penn State University in University Park, Pennsylvania, told Medscape Medical News.

“For our study, we wanted to expand the scope of knowledge in this area by investigating the issue prospectively in a large cohort with multiple LDL cholesterol measurements to capture variation over time,” first author Chaoran Ma, a nutritional sciences graduate student at Penn State, added in a news release.

The findings were published online July 2 in Neurology.

Less Rigid Targets Warranted?

The investigators assessed 101,510 participants in the Kailuan study in China.

At baseline between June 2006 and October 2007, enrollees completed a standardized questionnaire and underwent physical exams and laboratory testing, including LDL values. Assessments were repeated in 2008, 2010, and 2012.

The researchers excluded individuals without full LDL cholesterol results, as well as those diagnosed with stroke, myocardial infarction, or cancer at baseline.

Almost 14% of the 96,043 remaining participants had an LDL cholesterol value below 70 mg/dL.

During the 9 years of follow-up, 753 participants developed a hemorrhagic stroke. Within this group, 179 participants (24%) had LDL cholesterol below 70 mg/dL before the onset of disease.

The researchers controlled for age, sex, education, occupation, physical activity, smoking, alcohol intake, and relevant medical history.

Results showed an adjusted hazard ratio (HR) of 1.65 (95% confidence interval [CI], 1.32 – 2.05) for risk of developing ICH in the below 70 mg/dL group compared with those who had LDL concentrations of 70 to 99 mg/dL.

For participants with even lower LDL cholesterol concentrations (between 50 and 69 mg/dL), the risk was even more pronounced (HR, 2.69; 95% CI, 2.03 – 3.57).

Interestingly, the results did not change significantly when the investigators excluded those who were taking cholesterol-lowering medications or anticoagulants.

In addition, the risk for ICH was similar when outcomes in the reference LDL group (70 to 99 mg/dL) were compared to the group with LDL concentrations of 100 mg/dL or greater.

Gao said he was not surprised that lower LDL levels were associated with higher ICH risk.

"Cholesterol has a key role in the structural formation of cell membranes. Very low LDL could lead to erythrocyte fragility," he said.

Research has shown that LDL is also involved in the pathways of coagulation function and cerebral amyloid, "which are also important for hemorrhagic pathogenesis."

The researchers note that one interpretation of the results is that a "less stringent" target LDL cholesterol range of 70 to 99 mg/dL "might be more appropriate to obtain a better balance between cardiovascular disease and ischemic and hemorrhagic risks…in patients at higher ICH risk."

However, said Gao, it is important to take an individualized approach to patient management.

"I don’t think there is only one correct answer for everyone with different backgrounds in ethnicity, medical/health history, and lifestyle," he said.

"Treatment/prevention strategies should be personalized," Gao added. "[Patients] should discuss this with their doctor to develop an appropriate approach to obtain better balance between cardiovascular disease and ischemic and hemorrhagic stroke risks."

As a caveat, Gao noted another possible explanation for the findings.

"Although previous experimental studies suggest that low LDL-C could be a risk factor for ICH, it is also important to explore or exclude another possibility: it is merely a preclinical biomarker of ICH. In other words, it is due to some pathogenic changes that occur before onset of ICH and also lead to low LDL-C status," he said.

Unanswered Questions

Commenting for Medscape Medical News, Mitch Elkind, MD, Department of Neurology at Columbia University, New York City, and chair of the American Stroke Association advisory committee, said the study was well done "and definitely adds to the literature."

The generalizability of the findings, however, is "less clear," said Elkind, who was not involved with the study.

Previous researchers have also identified elevated ICH risks in large Asian populations, but whether these associations relate to differences in diet or genetics, or because hemorrhagic stroke is more common in Chinese individuals, remains unknown, Elkind added.

In March, he commented on a study in Nature Medicine that evaluated both ICH and ischemic stroke risk based on genetics in a Chinese population. He noted the net benefit of lowering LDL cholesterol to prevent the more common ischemic form of stroke outweighed, in general, the risk of ICH associated with low LDL.

"To me, as a clinician, the message is there may be a risk there, especially in Asians, but hemorrhage is still a less common event than ischemic stroke and so the benefits of being on LDL-lowering therapy might outweigh the risks for now," Elkind said.

Also commenting for Medscape Medical News, Pamela Rist, ScD, a researcher in preventative medicine at Brigham & Women's Hospital in Boston, Massachusetts, called the study interesting and said it "adds to the growing body of work" on the association between low LDL levels and risk of hemorrhagic stroke.

Assessing multiple LDL measurements over time was a strength of the study because it "allowed them to examine the association between average LDL level and risk of ICH," added Rist, who was not associated with the current research.

Rist was, however, the lead author of a study published in April that showed a similar link between low LDL cholesterol and elevated hemorrhagic stroke risk among nearly 28,000 women followed for 20 years, as previously reported by Medscape Medical News.

The current research raises some unanswered questions, she added.

"The authors try to extend their findings to suggest a less stringent LDL target among those at high risk of ICH, but the article does not provide additional guidance on how to identify these individuals, and does not perform formal analyses to determine how to best balance the potential risk for atherosclerotic events with the risk for ICH," Rist noted.

"It would be interesting to explore in future studies how changes in LDL levels over time may influence ICH risk," she said.

The study was funded by a startup grant from the College of Health and Human Development and the Department of Nutritional Sciences at Penn State University, and by the Institute for CyberScience Seed Grant Program at Penn State University. Gao reports having received funding from the NIH/National Institute of Neurological Disorders and Stroke. Elkind and Rist have disclosed no relevant financial relationships.

Neurol. Published online July 2, 2019. Abstract

Follow Damian McNamara on Twitter: @MedReporter. For more Medscape Neurology news, join us on Facebook and Twitter