Prediabetes Linked to Higher MACE Risk

Patients with prediabetes have a heightened risk of major adverse cardiovascular events, findings from a large, retrospective study suggest.

Through up to 14 years of follow-up, the MACE rate was 18% in patients who remained prediabetic and 11% in those who maintained normal blood glucose levels (P < 0.0001). The highest rate was seen in patients with diabetes (23%), which is a well-known risk factor for adverse cardiovascular outcomes.

Adrian Michel, MD (Beaumont Health, Royal Oak, MI), who is set to report the findings on May 16 during the virtual American College of Cardiology 2021 Scientific Session, noted that another study from his group showed that cardiovascular risk remained high even in prediabetic patients who normalized their blood glucose levels. Considering that, he told TCTMD, “I think we’ve got to really focus on preventing even getting into the prediabetic range in the first place.”

That might be a tough task, he acknowledged, and the best way to manage patients once they have prediabetes remains unclear. Further studies are needed to determine whether a conservative approach should be used to try to prevent progression to diabetes or whether more-aggressive treatment should be applied to normalize glucose levels with the ultimate aim of improving patient outcomes, he said.

Samuel Dagogo-Jack, MD (University of Tennessee Health Science Center, Memphis), endorsed the idea of acting earlier to identify patients at risk for developing prediabetes and taking steps to prevent blood glucose from rising any further.

He also called for the medical community to take prediabetes more seriously, pointing out that a link between prediabetes and adverse cardiovascular outcomes has been known for decades. In the 1980s, results from the Paris Prospective Study showed that working men with plasma glucose levels in the prediabetic range had an increased risk of coronary heart disease death over long-term follow-up, he said, adding that those data have been largely forgotten in the years since.

“We should not practice out of ignorance that a given individual can only be classified in terms of whether they have normal glucose or they have diabetes,” Dagogo-Jack told TCTMD. “The intermediate stage of prediabetes is a very toxic milieu for the initiation and propagation of potentially fatal complications, including heart attack, stroke, peripheral vascular disease, eye damage, and kidney damage. Every complication you find in people with long-standing diabetes has been documented in people with prediabetes.”

That may come as news to many physicians, said Dagogo-Jack, who described himself as “essentially a prediabetologist.” He bemoaned “the fact that probably 90% of practicing physicians are not as ginned up and motivated about doing something for prediabetes as I am or as I would like to see.”

Inflammation at Play

For the study, Michel and his colleagues performed a chart review of 108,086 adults treated in the Beaumont Health system between 2006 and 2020. They were divided into three groups based on whether they had normal glucose levels, prediabetes, or diabetes throughout the study period. MACE were identified using diagnostic codes.

I think we’ve got to really focus on preventing even getting into the prediabetic range in the first place. Adrian Michel

Asked what might explain the greater risk of MACE in patients with prediabetes, Michel pointed to inflammatory processes spurred on by the condition, noting that some of the inflammatory biomarkers elevated in diabetes have also been shown to be higher in prediabetes. “Diabetes we know does that, and that causes damage to the vessels, which causes plaque buildup, which can ultimately cause those events,” Michel said.

Dagogo-Jack said the mechanisms need to be studied more definitively, but agreed low-grade inflammation could be one of them. Glucose itself is likely a factor, but it can’t be the only one, he said, pointing also to metabolic syndrome and morphological changes to fat cells that could lay the groundwork for clinical CVD several years in the future.

Heart disease, he said, is “an insidious process and prediabetes represents part of the spectrum of toxic evolution of macrovascular as well as microvascular diseases.”

Don’t Count Out Treatment

Though the findings from Michel’s group indicate that patients with prediabetes still had a heightened cardiovascular risk after getting their glucose levels under control, Dagogo-Jack said the potential benefit of treatment should not be discounted. To get the maximum impact, physicians should target all problematic risk factors for cardiovascular disease and not just glucose levels, as was done in the Steno series of studies in Scandinavia, he suggested. The original Steno study, for instance, showed that an intervention targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, as well as secondary prevention of CVD with aspirin, lowered the risk of CVD in patients with type 2 diabetes and microalbuminuria.

“We should go and modify all of the risk factors and we will see results,” Dagogo-Jack said.

But he circled back to the idea that efforts should be made to prevent people from getting to the point where treatment could be necessary. The question, he said, is how best to do that.

“The predictors of transition from normal glucose to prediabetes need to be more fully understood before we can talk about preventing prediabetes in the first place,” Dagogo-Jack said. He highlighted the importance of figuring this out, noting that there are about 90 million patients with prediabetes in the United States and about 380 million worldwide and that this group will progress to diabetes at an average rate of about 10% per year.

What might need to happen to get this problem under control, he suggested, is to better refine glucose-based risk categories beyond normal, prediabetes, and diabetes. “I have used the term pre-prediabetes in a couple of my publications to sensitize people or to be evocative that before prediabetes there is a stage of pre-prediabetes that is different from normal glucose,” he said. This group needs more attention in order to stave off prediabetes and ultimately diabetes.

The results from Michel et al “argue strongly in favor of preventing people from even becoming prediabetic, and that task is challenged by a lack of total understanding of what makes an individual with normal glucose initially become prediabetic. But research is beginning to shed light on that earliest stage of glucose abnormalities,” Dagogo-Jack said.

For now, he said, “the number one thing is for practicing physicians to diversify their understanding of blood glucose abnormalities to increasingly flag prediabetes as a toxic state. . . . The prediabetes element is currently misperceived as a benign state, and the more we can have studies such as this one and other publications debunk that benign status of prediabetes, the better it will be for society.”