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Lower levels of low-density lipoprotein (LDL) cholesterol were tied to a higher risk of intracerebral hemorrhage (ICH), an epidemiological study in northern China showed.

People with LDL cholesterol concentrations under 70 mg/dL had a significantly higher risk of developing hemorrhagic stroke than people with LDL levels from 70 through 99 mg/dL, reported Xiang Gao, MD, PhD, of Pennsylvania State University in University Park, and coauthors.

After data adjustment, hazard ratios were 1.65 (95% CI 1.32-2.05) for people with LDL concentrations of 50 to 69 mg/dL and 2.69 (95% CI 2.03-3.57) for concentrations under 50 mg/dL, they wrote in .

"Previous studies have suggested that low LDL cholesterol concentration was associated with high ICH risk," Gao told 番茄社区app. "However, long-term safety -- such as risk of hemorrhagic stroke following the more intensive lipid-lowering -- remains uncertain to date."

Earlier research also was based on a single assessment of LDL, and "it remains unknown whether average LDL cholesterol concentration over time could be associated with altered intracerebral hemorrhage risk," Gao added.

In April, for example, pre-randomization assessment of LDL data from the showed that women with LDL cholesterol under 70 mg/dL had 2.17 times the risk of hemorrhagic stroke than women with LDL levels from 100 through 129.9 mg/dL.

Studies like these do not mean there's a causal relationship between low LDL and ICH, cautioned Michael Koren, MD, of the Jacksonville Center for Clinical Research in Florida, who was not involved with the research.

"This new study strongly suggests that very low baseline LDL levels are a marker for ICH risk, not the cause," Koren told 番茄社区app.

"Of importance to clinicians, it showed a similarly strong association between low baseline LDL and ICH after removing patients taking cholesterol drugs and anticoagulants from the analysis, indicating that these drug classes are not responsible for the findings," he said.

The population that showed the highest ICH risk "differed from other cohorts in that they smoked less, drank less alcohol, and reported less physical activity, use of antihypertensive agents, and high salt intake," he added. "The low LDL cohort also had the highest high-sensitivity C-reactive protein levels."

In their analysis, Gao and colleagues looked at 96,043 participants with no previous history of stroke, heart attack, or cancer in the community-based multicenter Kailuan study in the industrialized city of Tangshan, China. This cohort had LDL cholesterol levels measured when the study began in 2006 and yearly after that for 9 years, and reports of hemorrhagic stroke were confirmed by medical records.

During the 9-year follow-up period, the researchers identified 753 cases of incident ICH. Risk of ICH was similar for people with LDL levels from 70 to 99 mg/dL and people with levels of 100 mg/dL or higher.

In contrast, people with LDL concentrations under 70 mg/dL had a significantly higher risk of developing ICH than people with LDL levels of 70 to 99 mg/dL, even after factoring in age, sex, body mass index, hypertension, and drinking status. Excluding people who used cholesterol-lowering agents and anticoagulants did not change the results.

A recent meta-analysis of statin clinical trials showed an insignificant association between statin therapy and ICH risk, the researchers noted. And a that included two trials of anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors did not show a link between these drugs and altered subsequent risk of ICH: in either study, the investigators did not identify any hemorrhagic stroke cases. Similar results showing insignificant associations between LDL and ICH also emerged in the and trials.

But "these currently available limited data should be interpreted with caution because of the short follow-up durations (1.0-6.0 years) and small sample size of hemorrhagic stroke incident cases," Gao and coauthors wrote. "As suggested by another meta-analysis of PCSK9 trials, the potential effects of PCSK9 'remain inconclusive for rarer CVD [cardiovascular disease] and non-CVD events such as hemorrhagic stroke,' which could be due to lack of statistical power."

Based on the Kailuan cohort analysis, LDL levels that range from 70 and 100 mg/dL might be optimal for ICH prevention, the researchers concluded. Findings are limited by the observational nature of the study and may not apply to settings and populations outside industrialized areas of China, they added.

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