A meta-analysis of observational studies and randomized controlled trials on the relationship between low-density lipoprotein cholesterol and lipid-lowering agents and the risk of stroke

The findings from this systematic review and meta-analysis can be useful to identify the optimal low-density lipoprotein cholesterol (LDL-C) range to prevent the risk of stroke and plan future studies with different LDL-C targets and lipid-lowering agents (LLAs).

Key Takeaway

This systematic review and meta-analysis evaluating the impact of LDL-C levels from cohort studies and LLAs from randomized controlled trials (RCTs) on the risk of different types of strokes demonstrated:

  • Non-significant trend towards a higher risk of hemorrhagic stroke for all investigated LDL-C levels.
  • Significantly higher risk of ischemic stroke with higher LDL-C levels (>70 mg/dL).
  • Large effect on all strokes and ischemic strokes, but no significant effect on hemorrhagic strokes by statin and non-statin LLAs.

Overall, the data did not show any significant association between LDL-C thresholds and different LLAs and the risk of hemorrhagic stroke.

  • However, most effects seen in the present analysis were subject to high levels of heterogeneity.
  • Thus, well-designed studies are still warranted to determine the effects of low to extremely low LDL-C levels on hemorrhagic stroke and the role of LLAs.

Why This Matters

  • The effects of dyslipidemia on the pathogenesis of stroke are less clear and the relationship between cholesterol and ischemic stroke is inconsistent.
  • The impact of LLAs on stroke types has also not been well established.
  • Due to the paucity of studies and conflicting findings, this meta-analysis was conducted to better understand the relationship between low LDL-C levels and various types of strokes based on findings from observational studies and the impact of LLAs and risk of different types of strokes based on RCTs.

Study Design

  • Prospective cohort studies and RCTs† published up to 1 September 2019 were searched using PubMed, Embase, and Scopus databases.
  • The primary exposure of interest for cohort studies was LDL-C level and primary outcomes were different types of strokes.
  • The primary outcome of RCTs was stroke
  • Meta-analyses were performed by levels of achieved LDL-C (≤1.3 mmol/L, 1.3 to <1.8 mmol/L, and ≥1.8 mmol/L), statin or non-statin groups, primary vs secondary prevention, and specific type of stroke—ischemic and hemorrhagic.

Key Results

Cohort studies:

Characteristics of included cohort studies:

  • Eleven cohort studies involving 355,591 patients with 11,888 events were included in the meta-analysis
  • All studies included both sexes and the mean follow-up duration was 9.9 years (range: 4.9–19 years)

Association between LDL-C levels and stroke observed in cohort studies:

  • The highest LDL-C quartile was not associated with stroke events vs the lowest LDL-C quartile (hazard ratio [HR] = 1.032; P = 0.412; n = 3 studies; I2 = 0%).
  • Patients in the highest LDL-C quartile had a lower risk of hemorrhagic strokes (HR = 0.913; P = 0.012; n = 7 studies; I2 = 0%) and a higher risk of ischemic stroke (HR = 1.105; P <0.001; n = 7 studies; I2 = 0%).
  • No significant association was seen between LDL-C and intracerebral hemorrhage events (HR = 0.99; P = 1.0; n = 2 studies; I2 = 0%).
  • Sensitivity analysis: Pooled effect estimates were similar for the association between LDL-C and hemorrhagic stroke (HR = 0.91) and LDL-C and ischemic stroke (HR = 1.10).

RCTs:

Characteristics of included RCTs:

  • Eighteen RCTs published between 2002 and 2018 involving 165,988 patients were included in the meta-analysis
  • Across studies, the number of patients ranged from 2,107 to 27,564 and the proportion of men ranged from 48.3–82.2%, with a mean age of 63.1 years
  • The mean follow-up duration from baseline to endpoint was 4.1 years
  • The baseline and achieved LDL-C levels were 2.25–4.1 mmol/L and 0.78–3.1 mmol/L, respectively
  LDL-C levels achieved Statin vs non-statin/combination therapy Primary vs secondary prevention
Effect of LLAs  ≤ 1.3 mmol/L 1.3  ≤ 1.8 mmol/L ≥1.8 mmol/L Statin Non-statin Primary Secondary
All strokes  RR = 0.81
p < 0.001
I2 = 27%
n = 3		 RR = 0.83
p = 0.299
I2 = 72%
n = 3		 RR = 0.88
p = 0.008
I2 = 53%
n = 13		 RR = 0.82
p = 0.011
I2 = 56%
n = 15		 RR = 0.81
p < 0.001
I2 = 0.0%
n = 4		 RR = 0.854
p < 0.001
I2 = 52.7%
n = 17		 RR = 0.90
p = 0.092
I2 = 24.5%
n = 2
Ischemic Strokes RR = 0.78
I2 = 0.0%
n = 3		 RR = 0.76
p = 0.104
I2 = 56.7%
n = 3		 RR = 0.75
p < 0.001
I2 = 0.0%
n = 4

RR = 0.76

I2 = 32%
p < 0.001
n = 6

 RR = 0.77
p < 0.001
I2 = 0.0%
n = 4		 - -
Hemorrhagic strokes‡ RR = 1.14
I2 = 43.6% 
n = 3		 RR = 1.20
p = 0.301
I2 = 0.0%
n = 2		 RR = 1.25
p = 0.289
I2 = 57.9%
n = 5		 RR = 1.23 
p = 0.219
I2 = 47.4%
n = 6		 RR = 1.16
p = 0.232
I2 = 16.5%
n = 4		 - -


LDL-C, low-density level-cholesterol; LLAs, lipid-lowering agents; RR, relative risk

Limitations

  • Relatively high heterogeneity was observed in the link between LDL levels and stroke and between studies.
  • There was no sufficient statistical power and low level of type I and II error for RCTs on hemorrhagic stroke.

*For additional details and inclusion and exclusion criteria for cohort studies/RCTs, please refer to the source publication Banach M, et al. †RCTs were also searched on Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science by Clarivate and www.clinicaltrials.gov register. ‡Statin therapy was compared with combination therapy

    1. Banach M, Shekoohi N, Mikhailidis DP, Lip GYH, Hernandez AV, Mazidi M. Relationship between low-density lipoprotein cholesterol, lipid-lowering agents and risk of stroke: A meta-analysis of observational studies (n = 355,591) and randomized controlled trials (n = 165,988). Arch Med Sci. 2022;18(4):912–929. doi: 10.5114/aoms/145970. PMID: 35832716.

MAT-KW-2200334/V1/NOV2022