Background & Aims: Although diabetes mellitus and hyperglycemia are considered to be possible risk factors for various types of malignancy, the epidemiologic evidence concerning gastric cancer is scarce. The aim of this study was to evaluate the impact of hemoglobin A1c (HbA1c) levels on gastric cancer occurrence and their interaction with Helicobacter pylori infection. Methods: A total of 2603 Japanese subjects aged ≥40 years were stratified into 4 groups according to baseline HbA1c levels (≤4.9%, 5.0%-5.9%, 6.0%-6.9%, and ≥7.0%) and followed up prospectively for 14 years. Results: During the follow-up, 97 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer significantly increased in the 6.0%-6.9% (5.1 per 1000 person-years; P < .05) and ≥7.0% groups (5.5 per 1000 person-years; P < .05) compared with the 5.0%-5.9% group (2.5 per 1000 person-years), whereas it was slightly but not significantly high in the ≤4.9% group (3.6 per 1000 person-years). This association remained substantially unchanged even after adjusting for the confounding factors including Helicobacter pylori seropositivity, (multivariate-adjusted hazard ratio [HR], 2.13; 95% confidence interval [CI]: 1.30-3.47 for the 6.0%-6.9% group and HR, 2.69; 95% CI: 1.24-5.85 for the ≥7.0% group). Among subjects who had both high HbA1c levels (≥6.0%) and Helicobacter pylori infection, the risk of gastric cancer was dramatically elevated (interaction term, P = .004). Conclusions: Our findings suggest that casual hyperglycemia is a risk factor for gastric cancer and is a possible cofactor increasing the risk posed by Helicobacter pylori infection.
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