Reevaluating Blood Glucose Levels for CV Risk with Gregg C. Fonarow, MD

Emerging research suggests that even blood glucose levels within the higher end of the “normal” range may increase cardiovascular disease (CVD) risk, prompting experts to reconsider current guidelines. In an editorial published in the American Heart Journal, Gregg C. Fonarow, MD, division of cardiology, Geffen School of Medicine at the University of California, Los Angeles, highlights studies showing a significant rise in cardiovascular events in individuals with fasting glucose levels between 95-99 mg/dL compared with those below 80 mg/dL.

In an interview with HCPLive, Fonarow proposes a revised classification system that stratifies glucose levels within the normal range to better determine CVD risk and guide clinical decision-making. He emphasizes that while lifestyle interventions—such as increased physical activity and dietary modifications—remain foundational, pharmacologic options like GLP-1 receptor agonists and SGLT2 inhibitors may be appropriate for certain high-risk individuals.

He also underscores the importance of shifting clinical perspectives to recognize the continuous nature of cardiovascular risk across biomarkers, much like LDL-C. By refining risk assessment strategies and implementing targeted interventions, Fonarow indicated clinicians may better prevent premature cardiovascular events and improve patient outcomes.

This transcript has been edited for clarity.

Your editorial highlights compelling evidence linking higher normal blood glucose levels to increased cardiovascular risk. Could you break down key highlights from those findings and what they revealed about that link?

Traditionally, there's been wide recognition that individuals with overt diabetes and blood sugar elevations into the range for which diabetes is diagnosed are at increased cardiovascular risk. In addition, it's been recognized that those individuals with fasting glucose levels of 100 to just below 126 mg/dL have fallen into a category of prediabetes. Those individuals have also been at increased risk for cardiovascular events, not quite to the degree of those with T2D, but with excess risk.

Those who have had fasting blood sugar levels below 100 mg/dL have been felt to be at lower cardiovascular risk. However, there have been recent studies that have suggested that those still falling within what is traditionally viewed as the normal range below 100 mg/dL, but on the higher end between 90 and 99 mg/dL, there are detectable increases in cardiovascular risk in those individuals. By virtue of this editorial viewpoint, we highlighted that increase in risk, proposed an actual potential staging system that integrates that risk increase, and importantly, highlighted how some of that risk comes about and that this increase in cardiovascular risk may be potentially modifiable.

It highlights how the higher range in fasting glucose levels that are still within what has traditionally been considered the normal range is associated with increased cardiovascular risk. Specifically, an increased risk of myocardial infarction and ischemic stroke.

You and your co-author proposed a revised classification of those glucose levels and how that new framework might better guide risk assessment or clinical decision-making. How does that compare with the current guidelines?

It's important to recognize that although this terminology is of glucose in the normal range, because it's below 100 mg/dL, there is still the potential for increased risk. Recognizing those individuals in that range, using a staging classification, and those falling into Stage Two may help with that assessment, along with other established cardiovascular risk factors, to identify a group of individuals for potential lifestyle modification. An increase in physical activity, focusing on a cardiovascular-healthy diet could be beneficial for those where their blood pressure is elevated, and more aggressive.

Lowering blood pressure by more intensive treatment of modifiable lipid risk factors. Recognizing this is imparting some additional cardiovascular risk makes this actionable in that having an appropriate lifestyle and potential medication modifications are beneficial and can be applied to those individuals now, together with their clinician recognizing that increase in cardiovascular risk.

You highlighted some lifestyle prevention steps, but what are the potential medical interventions and how do they address this for this patient population?

A lot of what is driving this increased risk is this marker for insulin resistance, so there are disruptions of circadian rhythm, but also things worsening, including insulin-resistant chronic inflammation and less favorable physical activity. Obesity is contributing and may be an additional factor by which an individual would decide on medication use, including GLP-1 RAs. An increase in cardiovascular risk associated with a glucose level in this high normal range may be a factor that goes into decision-making beyond lifestyle interventions. Adding a GLP-1 RA would be reasonable for that individual and that’s a medication that could be considered.

SGLT2 inhibitors are another class of medication used for overt diabetes, chronic kidney disease (CKD), and heart failure. Depending on the other indications that are present, it may favor the selection of an SGLT2 inhibitor in certain individuals with glucose in the high normal range, but not to where they're at overt pre-diabetes or T2D. Those are some examples of medications that may favorably improve both blood sugar levels and insulin resistance and help lower cardiovascular risk.

On a larger scale, with an increased focus on cardiovascular risk biomarkers like LP(a) or LDL-C, what would need to happen for this perspective on blood glucose level classification to influence clinical guidelines?

With a lot of guidance and guidelines, we tend to classify these continuous risk factors that influence the way they are or are not treated. We recognize that with LDL-C, there's a continuum in the difference in risk. For somebody with an LDL-C of 101 versus 99 mg/dL, the difference is small but categorically may make a big difference in whether the patient gets treated or not. The same thing applies to fasting blood sugar levels, and HbA1c, and there's really a continuum. This recognition of what we previously would categorize as normal would often take this out of the patient or clinician’s mind that it may still be imparting risk. That is true with regards to these continuous biomarkers, where this gradation in risk and all of this should be factored into the clinical decision-making.

It is very much analogous and looks at not just a single continuous risk factor, but a background of that individual's age, other risk factors, and continuous biomarkers of cardiovascular risk. This becomes very important, all the more so because cardiovascular disease remains the leading cause of death in both men and women. Much of those premature cardiovascular events are preventable should lifestyle modification together with appropriate pharmacologic therapy be applied and adhered to in individuals at risk. We need to aim to identify that risk, act on it, and translate that to meaningful clinical risk reduction.

We are constantly at the population level and individual level not adequately applying our knowledge base to where there are lots of individuals at increased risks that have not been offered appropriate therapies that could help lower their risk. As a consequence, there are large number of cardiovascular events that continue to occur that could have been prevented with more precise and personalized cardiovascular risk assessment and the deployment of patient-centered cardiovascular risk reduction strategies.

Fonarow reports relevant disclosures with Bayer, Cytokinetics, Edwards Life Sciences, Johnson & Johnson, Merck, Novartis, and others.

References

1. Ebrahimi M, Fonarow GC. Higher levels of glucose within the normal range and cardiovascular risk: A landscape beyond diabetes and prediabetes. Am Heart J. 2025;283:1-4. doi:10.1016/j.ahj.2025.01.008

2. Shaye K, Amir T, Shlomo S, Yechezkel S. Fasting glucose levels within the high normal range predict cardiovascular outcome. Am Heart J. 2012;164(1):111-116. doi:10.1016/j.ahj.2012.03.023