Relationship Between Glycated Hemoglobin and Stroke Risk: A Systematic Review and Meta-Analysis

Background: Diabetes mellitus is a major risk factor for ischemic stroke. Rising hemoglobin A_1c (HbA_1c) levels are associated with microvascular diabetes mellitus complication development; however, this relationship has not been established for stroke risk, a macrovascular complication.

Methods and results: We conducted a systematic review and meta-analysis of observational cohort and nested case-control cohort studies assessing the association between rising HbA_1c levels and stroke risk in adults (≥18 years old) with and without type 1 or type 2 diabetes mellitus. Random-effects model meta-analyses were used to calculate pooled adjusted hazard ratios (HRs) and their precision. The systematic review yielded 36 articles, of which 29 articles (comprising n=532 779 participants) were included in our meta-analysis. Compared to non-diabetes mellitus range HbA_1c (<5.7%), diabetes mellitus range HbA_1c (≥6.5%) was associated with an increased risk of first-ever stroke with average HR (95% confidence interval) of 2.15 (1.76, 2.63), whereas pre-diabetes mellitus range HbA_1c (5.7-6.5%) was not (average HR [95% confidence interval], 1.19 [0.87, 1.62]). For every 1% HbA_1c increment (or equivalent), the average HR (95% confidence interval) for first-ever stroke was 1.12 (0.91, 1.39) in non-diabetes mellitus cohorts and 1.17 (1.09, 1.25) in diabetes mellitus cohorts. For every 1% HbA_1c increment, both non-diabetes mellitus and diabetes mellitus cohorts had a higher associated risk of first-ever ischemic stroke with average HR (95% confidence interval) of 1.49 (1.32, 1.69) and 1.24 (1.11, 1.39), respectively.

Conclusions: A rising HbA_1c level is associated with increased first-ever stroke risk in cohorts with a diabetes mellitus diagnosis and increased risk of first-ever ischemic stroke in non-diabetes mellitus cohorts. These findings suggest that more intensive HbA_1c glycemic control targets may be required for optimal ischemic stroke prevention.