Additive Interaction of Hyperglycemia and Albuminuria on Risk of Ischemic Stroke in Type 2 Diabetes

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Abstract
OBJECTIVE—The study aims to test whether biological interaction between hyperglycemia and albuminuria can explain the inconsistent findings from epidemiological studies and clinical trials about effects of hyperglycemia on stroke in type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 6,445 Hong Kong Chinese patients with type 2 diabetes and free of stroke at enrollment were followed up for a median of 5.37 years. Spline Cox proportional hazard regression was used to obtain hazard ratio curves, which were used to identify cutoff points of A1C and spot urinary albumin–to–creatinine ratio for increased ischemic stroke risk. The identified cutoff point of A1C was used to check biological interaction between A1C and albuminuria (micro- and macroalbuminuria). The biological interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index. RESULTS—During the follow-up period, 4.45% (n = 287) of patients developed ischemic stroke. A1C was associated with increased hazard ratios of ischemic stroke in a near-linear manner except for two points—6.2 and 8.0%—where the slope between these two points accelerated. For A1C values <6.2%, the presence of micro/macroalbuminuria did not confer additional risk, while significant biological interaction between A1C and micro/macroalbuminuria for values ≥6.2% was observed (RERI 0.92, 95% CI 0.16–1.68, and AP 0.40, 0.01–0.78). CONCLUSIONS—A1C ≥6.2% and micro/macroalbuminuria interact to markedly increase the ischemic stroke risk, which explains a large proportion of risk in patients with type 2 diabetes harboring both risk factors.

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