Risk more than doubled when hemoglobin A1C levels increased from 5.0% to 5.7%, a range typically considered normal or healthy

A well-established marker of diabetes may signify heightened risk of heart disease at levels widely considered benign, finds a new study by scientists from Quest Diagnostics. The analysis provides new evidence for the role of metabolic dysfunction in cardiovascular disease and raises questions about the need for earlier intervention to preserve heart health.

Published in Endocrinology and Diabetes, the flagship journal of the American Association of Clinical Endocrinology, the study by scientists from Quest Diagnostics and the University of Colorado sought to investigate the relationship between hemoglobin A1C (A1C) levels at so-called normal or healthy levels and five modifiable biomarkers signifying cardiovascular disease risk: low-density cholesterol, ApoB, triglycerides, insulin resistance score and myeloperoxidase (MPO).

While the connection between metabolic dysfunction and cardiovascular disease is well established, the researchers theorized that early hyperglycemia, as measured by A1C, may increase risk of heart disease even when a patient’s A1C is in a normal or healthy level.

A1C is a blood test that measures the amount of glucose attached to an individual’s hemoglobin to gauge diabetes risk. A1C levels below 5.7% are considered normal, while those between 5.7%-6.4% are considered prediabetic and those at or above 6.5% are diabetic.

The scientists found that markers associated with cardiometabolic disease began to rise when A1C levels were as low as 5.0%, well below the established threshold for prediabetes or diabetes. Risk rose steadily with increasing A1C and more than doubled from 21% to 50% as A1C levels rose from 5.0% to 5.7%.

Put another way, for every 0.1% increase in A1C levels in the population, another 4% of individuals showed signs of cardiovascular disease risk based on biomarker results. In addition, the results of abnormal cardiovascular markers were “infrequently redundant,” and most patients had a single abnormal biomarker, suggesting risk may be highly personalized.

“About 50% of the patients in our study who had an A1C below 5.7% had one or more abnormal cardiovascular biomarker results, and risk increased as A1C levels rose,” said board-certified cardiologist and lead author Marc Penn, M.D., Medical Director of Cardiometabolic Health Clinical Solutions at Quest Diagnostics. “These are compelling data that suggest the current clinical focus on measuring A1C and low-density cholesterol alone means some patients may be reassured ‘everything is okay’ instead of receiving insights into their true risks.”

The findings suggest that relying solely on standard low-density lipoprotein cholesterol (LDL-C) and A1C measurements may not be sufficient for early risk assessment. Identifying individuals with early signs of cardiometabolic dysfunction could allow for timely lifestyle or pharmacological interventions to prevent or reverse the condition before a person is ever labelled with a disease.

The study examined data from 127,141 individuals who underwent testing for A1C and ApoB, a measure of plaque-forming lipid particles in a person’s blood, at the Quest Diagnostics Center of Excellence for Cardiometabolic Testing at Cleveland HeartLab between 2021 and 2022. Approximately 10,970 specimens were included in the final analysis. All test results were de-identified and aggregated for analysis. The mean age of the population was 61.6 years, with 52% female.

The study’s main strength was its large and diverse real-world data set. Its primary limitation was the inability to draw definitive conclusions about long-term clinical outcomes due to lack of access to medical records and the retrospective nature of the data.