Ldl Levels: Lower Numbers, Higher Hemorrhagic Stroke Risks?

Low-density lipoprotein cholesterol (LDL-C) is a known risk factor for atherosclerosis, and a common target of treatment for primary and secondary prevention of cerebrocardiovascular disease. However, there is an association between low LDL-C and total cholesterol and intracerebral hemorrhage (ICH).

Several studies have examined the association between low levels of cholesterol and the risk of ICH. Some studies have shown that participants with LDL-C of 140 mg/dL or higher had half the sex- and age-adjusted risk of death due to ICH compared to those with LDL cholesterol under 80 mg/dL. However, other studies have not demonstrated the same association between low LDL-C and ICH or hemorrhagic stroke.

The association between low LDL-C and ICH risk is not fully understood, but it is thought that low cholesterol may result in arterial medial layer smooth muscle cell necrosis and that the impaired endothelium may be more susceptible to microaneurysms, which are often found in ICH patients.

Recent studies have shown that the use of more intensive lipid-lowering therapy that achieved an LDL-C level lower than 55 mg/dl in patients with high cardiovascular risk is not associated with an increased risk of hemorrhagic stroke.

LDL-C levels and risk of intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is a subtype of stroke characterised by the formation of a hematoma within the brain parenchyma. It is associated with high mortality and disability rates. Cholesterol plays a key role in the structural formation of cell membranes, and low cholesterol concentration has been proposed as a potential risk factor for ICH. On the other hand, excessive levels of cholesterol in the blood, especially its low-density lipoprotein (LDL) fraction, are a known risk factor for atherosclerosis development and an increased rate of cardiovascular events. Thus, the relationship between LDL cholesterol and ICH is complex, and further investigation is needed to determine the ideal LDL range for patients at risk of both atherosclerotic disease and haemorrhagic stroke.

LDL-C and ICH Risk: What the Data Says

Several studies have examined the association between low levels of LDL-C and the risk of ICH. Some studies have found an inverse relationship between LDL-C and ICH risk, while others have found no significant association. However, most of these studies have been limited by a small number of incident ICH cases and have been based on a single baseline LDL-C measurement, which may not capture fluctuations and changes in LDL-C concentrations over time.

A recent large prospective study in China included 96,043 healthy participants who were free from stroke, myocardial infarction, and cancer at baseline. The study found that participants with LDL-C concentrations below 70 mg/dL had a significantly higher risk of developing ICH compared to those with LDL-C concentrations of 70-99 mg/dL. The adjusted hazard ratios were 1.65 (95% CI 1.32-2.05) for LDL-C concentrations of 50-69 mg/dL and 2.69 (95% CI 2.03-3.57) for LDL-C concentrations below 50 mg/dL. This association between lower LDL-C and higher ICH risk was consistent for both deep and non-deep hematoma.

In contrast, a meta-analysis of statin clinical trials found no significant increase in ICH among treated patients. However, a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) clinical trial indicated that atorvastatin use was associated with an increased risk of ICH in patients enrolled after experiencing a haemorrhagic stroke. Additionally, a recent meta-analysis of non-statin clinical trials of further lowering LDL-C in patients starting with very low levels showed a non-significant positive association between LDL-C lowering and increased risk of haemorrhagic stroke.

While the association between low baseline LDL-C and the occurrence of ICH seems to be recognised, the causal association between LDL-C lowering therapeutic strategies and ICH remains uncertain. Due to the low haemorrhagic stroke incidence in the different trials and meta-analyses presented so far, more data with longer follow-up periods are needed to determine whether LDL-C lowering indeed increases the risk of ICH. In the meantime, a cautious approach is advised when considering aggressive LDL reduction in patients who are considered at high risk for ICH. This includes individuals with previous haemorrhagic strokes, uncontrolled hypertension, or imaging evidence of cerebral amyloid angiopathy using brain MRI.

Lipid levels and the risk of haemorrhagic stroke among women

Haemorrhagic strokes are less common than ischaemic strokes, but they still occur in large cohorts. There is a need to understand the risk factors for stroke among women, as the burden of stroke is considered higher for women than men.

Methods

A prospective cohort study was performed among 27,937 women enrolled in the Women's Health Study. The study examined the association between lipid levels and haemorrhagic stroke risk among women. The women had measured total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), as well as triglycerides. Strokes were confirmed by medical record review.

Results

During a mean of 19.3 years of follow-up, 137 haemorrhagic strokes occurred. After multivariable adjustment, compared to those with LDL-C levels of 100-129.9 mg/dL, those with LDL-C levels <70 mg/dL had 2.17 times the risk of experiencing a haemorrhagic stroke. There was a suggestion, although not significant, of increased risk for those with LDL-C levels ≥160 mg/dL. Women in the lowest quartile of triglycerides had a significantly increased risk of haemorrhagic stroke compared to women in the top quartile after multivariable adjustment. No significant associations were observed between total cholesterol or HDL-C levels and haemorrhagic stroke risk.

LDL-C levels <70 mg/dL and low triglyceride levels were associated with an increased risk of haemorrhagic stroke among women.

LDL-C levels below 55 mg/dl and risk of haemorrhagic stroke

LDL-C Levels Below 55 mg/dl and Risk of Hemorrhagic Stroke

Low-density lipoprotein cholesterol (LDL-C) is a known risk factor for atherosclerosis and a common target for the primary and secondary prevention of cerebrocardiovascular disease. However, there are concerns that very low LDL-C levels may increase the risk of hemorrhagic stroke. The currently suggested LDL-C goal for very high-risk patients is *55 mg/dL. This review aims to evaluate the effect of LDL-C levels below 55 mg/dL on the risk of hemorrhagic stroke.

Methods

A meta-analysis was performed, including randomized trials that achieved LDL-C levels under 55 mg/dL in more intensive lipid-lowering arms, regardless of the lipid-lowering drug used.

Results

Eight eligible trials including 122,802 patients were identified. A total of 62,526 subjects received more intensive lipid-lowering therapy, while 60,276 subjects were allocated to the respective control arms. There were no significant differences in the incidence of hemorrhagic stroke between the group that received more intensive lipid-lowering therapy (achieved LDL-C level *55 mg/dL) and the group that received a less intensive scheme (OR 1.05, 95% CI 0.85-1.31). The statistical heterogeneity was low (I2 = 2%).

Discussion

The use of more intensive lipid-lowering therapy to achieve LDL-C levels below 55 mg/dL in patients with high cardiovascular risk does not appear to be associated with an increased risk of hemorrhagic stroke. The challenging lipid goals recommended by the new guidelines seem consistent, considering the cardiovascular benefits and safety observed with very low LDL-C values. However, due to the low incidence of hemorrhagic stroke in the trials, more data with longer follow-up periods are needed to confirm these findings.

LDL-C levels and risk of ischaemic and haemorrhagic stroke in Chinese adults

Low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for atherosclerosis and a common target for the primary and secondary prevention of cerebrocardiovascular disease. Lowering LDL-C levels is a key strategy in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, the optimal LDL-C level is not well-established in Chinese adults.

LDL-C levels and risk of ischaemic and haemorrhagic stroke

A 2021 study found that Chinese adults with LDL-C concentrations below 70 mg/dL who were not receiving lipid-lowering therapy were still at high risk of ischaemic and haemorrhagic stroke. The study identified very low LDL-C concentrations and poorly controlled blood pressure as the main predictors of stroke risk.

Another study, which followed Chinese participants for about 20 years, found that LDL-C levels below 70 mg/dL were associated with an increased risk of haemorrhagic stroke, especially in patients with uncontrolled hypertension. The study also found that LDL-C levels between 70 and 99 mg/dL had a reasonably low ASCVD risk without an excess risk of other life-threatening diseases.

A 2023 study found that LDL-C levels below 1.4 mmol/L or 1.8 mmol/L were associated with an increased risk of intracranial haemorrhage in patients who had an ischaemic stroke.

While lowering LDL-C levels is an important strategy for preventing ASCVD, LDL-C levels below 70 mg/dL or 1.8 mmol/L may increase the risk of haemorrhagic stroke, especially in Chinese adults with uncontrolled hypertension. Therefore, a cautious approach and individualised therapy strategy are advised when considering aggressive LDL reduction.

LDL-C levels and risk of haemorrhagic stroke: a systematic review and meta-analysis

Haemorrhagic stroke, a subtype of stroke, is a condition where a haematoma is formed within the brain parenchyma. It is associated with high mortality and disability rates. Cholesterol plays a key role in the structural formation of cell membranes, and low cholesterol concentration has been proposed as a potential risk factor for haemorrhagic stroke. However, excessive levels of cholesterol in the blood, especially low-density lipoprotein (LDL-C), are a known risk factor for atherosclerosis development and an increased rate of cardiovascular events. Therefore, the relationship between LDL-C levels and the risk of haemorrhagic stroke has been the subject of several studies and meta-analyses.

LDL-C and Haemorrhagic Stroke Risk: Study Findings

Several studies have examined the association between low LDL-C levels and the risk of haemorrhagic stroke, with inconsistent results. Some studies have found an inverse relationship between LDL-C and haemorrhagic stroke risk, while others have found no association.

One meta-analysis of 23 prospective studies with 1,430,414 participants found a statistically significant inverse association between total cholesterol (TC) level and haemorrhagic stroke risk. Specifically, a 1 mmol/L increment in TC concentration was associated with a 15% decreased risk of haemorrhagic stroke. Lower LDL-C concentrations were also associated with a higher risk of haemorrhagic stroke. However, no significant association was found between high-density lipoprotein cholesterol (HDL-C) and haemorrhagic stroke risk.

Another meta-analysis of seven large cohort studies with 476,173 participants and 7,587 haemorrhagic stroke cases showed that a 10 mg/dL increase in LDL-C was associated with a 3% lower risk of haemorrhagic stroke. This association was more pronounced in Asians compared to Caucasians.

In contrast, a prospective cohort study of 27,937 women found that LDL-C levels <70 mg/dL were associated with a 2.17 times higher risk of haemorrhagic stroke compared to LDL-C levels of 100-129.9 mg/dL. However, no significant increase in risk was seen for LDL-C levels of 130-159.9 mg/dL or 70-99.9 mg/dL.

While some studies suggest an inverse relationship between LDL-C levels and haemorrhagic stroke risk, the evidence is mixed, and more research is needed to understand the underlying pathogenesis and determine the optimal LDL-C range to minimise haemorrhagic stroke risk in different populations.

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