Low LDL-c and TG levels associated with risk of hemorrhagic stroke in women

Lipid levels and the risk of hemorrhagic stroke among women

Literature - Rist PM, Buring JE, Ridker PM, et al., - Neurology 2019. DOI: https://doi.org/10.1212/WNL.0000000000007454

Introduction and methods

Although hypercholesterolemia is a risk factor for ischemic stroke, a meta-analysis observed that total and LDL cholesterol levels were inversely associated with the risk of hemorrhagic stroke. No association was seen for HDL-c [1]. Moreover, a meta-analysis of statin trials revealed that a 1 mmol/L reduction in LDL-c was associated with a 15% increased risk of hemorrhagic stroke [2]. Other studies suggested that low triglyceride (TG) levels may also increase hemorrhagic stroke risk [3-5].

Several questions regarding these observations remain unanswered. For instance, no sex-stratified data have been presented due to low numbers of events among women. The burden of stroke is, however, considered to be higher in women than in men [6]. It is therefore important to identify risk factors for stroke in women. Moreover, the association between lipid levels and stroke were not specified by hemorrhagic stroke subtypes. Finally, no distinction was made between individuals with elevated lipid levels and those with optimal or near optimal lipid levels.

This study evaluated the association between lipid levels (total cholesterol [TC], LDL-c, TG and HDL-c) and risk of hemorrhagic stroke in the large, prospective Women’s Health Study (WHS) [7,8]. WHS is a randomized, double blind, placebo-controlled trial of low-dose aspirin and vitamin E for the primary prevention of CV disease and cancer among 39876 US female health professionals of at least 45 years old. Lipid levels were determined in a blood sample taken prior to randomization, in 27937 samples. Strokes were classified as ischemic, hemorrhagic and unknown types. Hemorrhagic stroke was further divided into intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) or intraventricular hemorrhage (IVH). During a mean of 19.3 years of follow-up, 137 incident hemorrhagic strokes were reported (ICH: 85, SAH: 43 and 3 IVH, combination ICH/SAH: 3 and 3 due to a procedure).

Main results

  • A U-shaped relationship between LDL-c and hemorrhagic stroke risk was observed.
  • After multivariable adjustment, those with LDL-c <70 mg/dL had over two-fold risk of experiencing a hemorrhagic stroke, as compared with women with LDL-c 100-129.9 mg/dL (RR: 2.17, 95%CI: 1.05-4.48).
  • Those with LDL-c ≥160 mg/dL showed a non-significantly increased risk of stroke, as compared with those with LDL-c 100-129.9 mg/dL (RR: 1.53, 95%CI: 0.92-2.52).
  • As compared with the reference group with LDL-c 100-129.9 mg/dL, no significant differences in the risk of hemorrhagic stroke was seen in those with LDL-c 70-99.9 mg/dL (RR: 1.25, 95%CI: 0.76-2.04) or LDL-c 130-159.9 mg/dL (RR: 1.14, 95%CI: 0.72-1.80).
  • ICH showed a similar risk pattern, with the highest event risk seen in women with LDL-c <70 mg/dL (RR: 2.32, 95%CI: 0.95-5.65), followed by those with LDL-c ≥160 mg/dL (RR: 1.71, 95%CI: 0.95-3.09).
  • SAH also showed the highest risk in those with LDL-c <70 mg/dL (RR: 2.21, 95%CI: 0.62-7.88), but this risk was not significantly elevated.
  • The lowest TG quartile (fasting: ≤74 mg/dL and non-fasting: ≤85 mg/dL) showed a significantly increased risk of hemorrhagic stroke as compared with women in the highest quartile, after multivariable adjustment (RR: 2.00, 95%CI: 1.18-3.39). Other quartiles did not show significant associations. Low TG levels were significantly associated with a higher risk of SAH, but not of ICH.
  • No significant associations were observed between TC or HDL-c levels and risk of hemorrhagic stroke.


In a large, prospective cohort of middle-aged to elderly women, an increased risk of hemorrhagic stroke was seen among those with LDL-c <70 mg/dL and a potential increase in risk among those with LDL-c ≥160 mg/dL. Low TG levels were also associated with a higher risk of hemorrhagic stroke, specifically the subarachnoid subtype. Total and HDL cholesterol were not significantly linked to the risk of hemorrhagic stroke. These findings suggest that women with very low LDL-c or TG levels should be monitored for other modifiable risk factors for hemorrhagic stroke, such as hypertension and smoking, to minimize their overall risk of hemorrhagic stroke.


1. Wang X, Dong Y, Qi X, Huang C, Hou L. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke 2013;44:1833–1839.

2. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–590.

3. Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD, CushmanM. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke 2007; 38:2718–2725.

4. Wieberdink RG, Poels MMF, Vernooij MW, et al. Serum lipid levels and the risk of intracerebral hemorrhage: the Rotterdam Study. Arterioscler Thromb Vasc Biol 2011;31:2982–2989.

5. Bonaventure A, Kurth T, Pico F, et al. Triglycerides and risk of hemorrhagic stroke vs. ischemic vascular events: the Three-City Study. Atherosclerosis 2010;210:243–248.

6. Reeves MJ, Bushnell CD, Howard G, et al. Sex di erences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008;7:915–926.

7. Ridker PM,CookNR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293–1304.

8. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294:56–65.

Find this article online at Neurology

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free