Prediabetes Defined by First Measured HbA_1c Predicts Higher Cardiovascular Risk Compared With HbA_1c in the Diabetes Range: A Cohort Study of Nationwide Registries

Objective: To assess the risk of major adverse cardiovascular events (MACE), all-cause mortality, and initiation of medical treatment in subjects with prediabetes according to first-time measured HbA_1c.

Research design and methods: Through registry databases, we identified 326,305 Danish patients with a first HbA_1c between 40 and 51 mmol/mol (5.8-6.8%) from 2011 to 2017. After exclusion of patients with prior disease, 84,678 patients were followed 12 months after first HbA_1c measurement. Cox regression models were used to estimate hazard ratios (HRs) of MACE and standardized absolute risks. Cumulative incidences were used to analyze initiation of glucose-lowering, antihypertensive, cholesterol-lowering, and antithrombotic medication.

Results: The 12-month risk of MACE and all-cause mortality increased gradually with increasing HbA_1c until 47 mmol/mol (6.5%). In comparisons of subjects with HbA_1c 40-41 mmol/mol (5.8-5.9%), subjects with HbA_1c 46-47 mmol/mol (6.4-6.5%) had a 0.79% (95% CI 0.33-1.24) higher standardized absolute risk and an HR of 2.21 (95% CI 1.67-2.92) of MACE. Patients with HbA_1c 48-49 mmol/mol (6.5-6.6%) had a 0.09% (95% CI -0.35 to 0.52) lower absolute risk and an HR of 1.33 (95% CI 0.87-2.05) of MACE. Initiation of medication was significantly lower among patients with HbA_1c of 46-47 mmol/mol (6.4-6.5%) than among patients with HbA_1c of 48-49 mmol/mol (6.5-6.6%).

Conclusions: In the Danish population screened for diabetes with HbA_1c, the highest risk of MACE and all-cause mortality was found in subjects with HbA_1c just below the diagnostic threshold for diabetes. Our results highlight the need for increased focus on the treatment of cardiovascular risk factors for subjects with prediabetes.