Diabetes Aside, HbA1c a Telling Indicator of Arterial Buildup

Glycated hemoglobin (HbA1c) could have prognostic value for people without diabetes and no history of cardiovascular disease (CVD), according to an observational study of nearly 4,000 middle-age individuals.

In the PESA study, HbA1c showed a graded, positive association with the prevalence and multi-territorial extent of subclinical atherosclerosis detected by vascular ultrasound and noncontrast cardiac CT, reported Valentin Fuster, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City and Centro Nacional de Investigaciones Cardiovasculares Carlos III in Madrid, and colleagues.

This association was independent of traditional cardiovascular risk factors and was significant in all prediabetes groups, even below the prediabetes cutoff (HbA1c 5.5%-5.6%; OR 1.36, 95% CI 1.03-1.80, P=0.033), Fuster’s group noted in the Journal of the American College of Cardiology.

A measure of protein glycation, HbA1c >6.5% is the accepted cutoff point for diagnosing diabetes, and an HbA1c of 5.7% to 6.4% is the range for prediabetes.

“The clear association between HbA1c and SA [subclinical atherosclerosis] suggests that any primary intervention to reduce HbA1c levels could potentially benefit millions of people with HbA1c below the diabetes diagnosis threshold by reducing not only the risk of developing T2DM [type 2 diabetes mellitus], but also the extent of SA,” the investigators wrote.

Lifestyle and medical interventions alike may be considered in this context, they suggested.

In the study, high HbA1c levels were associated with a significantly increased risk of subclinical atherosclerosis in people who were deemed low risk according to the Systematic Coronary Risk Estimation (SCORE) algorithm (P<0.001), though this was not the case in people with moderate risk (P=0.335).

“This observation is not surprising given the stronger association of risk factors like dyslipidemia and hypertension, found more commonly in intermediate-risk individuals, with atherosclerosis. However, this finding in no way impugns the study’s major conclusion: risk of [subclinical atherosclerosis] in low-risk individuals is graded according to HbA1c, even at levels below the pre-diabetes threshold,” wrote Raul Santos, MD, PhD, of the Heart Institute, University of São Paulo Medical School in Brazil, and colleagues in an accompanying editorial.

In any case, Fuster and team reported that adding HbA1c to SCORE or atherosclerotic CVD predictors modified the risk calculation in most risk categories.

Fasting plasma glucose, on the other hand, showed no association with subclinical atherosclerosis.

“The observations from this study and others may provide a rationale for a clinical trial testing novel diabetes therapies focused more on presence and extent of [subclinical atherosclerosis] rather than an elevated HbA1c per se,” noted Santos and co-authors.

“Might we envision the implementation of novel evidence-based pharmacologic therapies that not only reduce glucose but, more importantly, prevent both CVD events and development of diabetes in those without T2DM?” they added.

The editorialists highlighted GLP-1 receptor agonists as promising agents.

PESA study participants were all employed at the Santander Bank Headquarters in Madrid. The 3,973 people included in the present analysis (mean age 45.7 years, 37.7% women) were generally at low or moderate cardiovascular risk.

Mean HbA1c was 5.4%, and the median SCORE index predicted a 0.35% risk of cardiovascular death over 10 years.

Notably, even the low-risk group was found to have a subclinical atherosclerosis prevalence of 56.5%.

Fuster’s team acknowledged that the observational nature of the study left room for possible residual confounding, and that they used CVD risk scores designed to estimate cardiovascular events, not subclinical atherosclerosis.

Furthermore, the fairly homogenous PESA population may not be representative of other groups, the authors cautioned.