Patients with glycated hemoglobin levels (HbA1c) just below the diagnostic threshold for diabetes have the highest risk of major adverse cardiovascular events (MACE) and all-cause mortality, according to a study in Diabetes Care.
Using registry databases, investigators evaluated the risk of MACE, all-cause mortality, and initiation of medical treatment among Danish people with prediabetes according to their baseline HbA1c level. The primary endpoint was the first occurrence of MACE, a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes. Secondary endpoints included all-cause mortality and initiation of treatment, such as of glucose-lowering medications.
A total of 84,678 patients with a first-time baseline measurement of HbA1c were included and categorized into 6 subgroups by HbA1c levels—40 to 41 mmol/mol (5.8%-5.9%), 42 to 43 mmol/mol (6.0%-6.1%), 44 to 45 mmol/mol (6.2%-6.3%), 46 to 47 mmol/mol (6.4%-6.5%), 48 to 49 mmol/mol (6.5%-6.6%), and 50 to 51 mmol/ mol (6.7%-6.8%). Participants’ median age varied from 58.4 years (interquartile range [IQR], 50.7-66.8) to 61.8 years (IQR, 53.3-70.3) between the groups.
After a 1-year follow-up, 799 individuals (0.94%) had a MACE. A dose-response relationship was observed between higher HbA1c and incident MACE in patients in the HbA1c range of 40 to 47 mmol/mol (5.8%-6.5%). The highest risk of MACE was found in the subgroup without diabetes, with HbA1c levels of 46 to 47 mmol/mol (6.4%-6.5%) (hazard ratio [HR], 2.21; 95% CI, 1.67-2.92).
Compared with individuals with an HbA1c level of 40 to 41 mmol/mol (5.8%-5.9%), a higher standardized absolute risk of MACE was found in the other 5 subgroups. The subgroup of HbA1c of 44 to 45 mmol/mol (6.2%-6.3%) and HbA1c 46 to 47 mmol/mol (6.4%-6.5%) had significantly higher risks, with differences of 0.31% (95% CI, 0.06-0.56) and 0.79% (95% CI, 0.33-1.24), respectively.
The risk of MACE in people who passed the threshold of prediabetes to diabetes (HbA1c 48 to 49 mmol/mol (6.5%-6.6%) and 50 to 51 mmol/ mol (6.7%-6.8%) had lower standardized absolute risks compared with the subgroup just under the threshold, with HbA1c levels of 46-47 mmol/mol (6.4%-6.5%) with 1.73% (95% CI, 1.33-2-22).
For the subgroup with the highest first measurement, HbA1c 50 to 51 mmol/mol (6.7%-6.8%), 514 (44%) patients initiated glucose-lowering medication, 317 (27%) initiated use of statins, and 231 (20%) initiated use of renin-angiotensin system inhibitors (RASi) within 1 year. For those just below the threshold of type 2 diabetes, 259 (8%) people from the subgroup with HbA1c 46 to 47 mmol/mol (6.4%-6.5%) began glucose-lowering medication, 383 (11%) began using statins, and 408 (12%) began using RASi within 1 year of their baseline measurement
The researchers noted that data for some modifiable risk factors, including exercise, smoking, alcohol intake, body mass index (BMI), and diet, were not available. Also, surveillance bias likely affected the results.
“Our study demonstrates an increased risk of MACE and all-cause mortality in the upper normal range of HbA1c as compared with HbA1c >48 mmol/mol (6.5%), the level typically prompting multifactorial treatment of type 2 diabetes,” the study authors wrote. “These results support the hypothesis that treatment for cardiovascular risk factors should start before type 2 diabetes develops and suggest that more attention and potentially evidence-based guidelines are needed in the management of prediabetes with better monitoring of this patient group.”
Yahyavi SK, Snorgaard O, Knop FK, et al. Prediabetes defined by first measured HbA1c predicts higher cardiovascular risk compared with HbA1c in the diabetes range: a cohort study of nationwide registries. Diabetes Care. Published online October 21, 2021. doi:10.2337/dc21-1062