José O. Alemán, MD, PhD, assistant professor of endocrinology at NYU Langone Health, recalls the daunting experience of facing an unknown and potentially deadly disease when the coronavirus disease (COVID-19) pandemic began sweeping through New York in March and April of 2020. “It became very clear that the experience in New York was going to be different from that of China and Italy,” says Dr. Alemán, who cared for patients in the COVID-19 wards of the Manhattan Campus of the VA New York Harbor Healthcare System.

Troubling Links to Obesity and Hyperglycemia

Older age had already emerged as a prognostic risk factor for COVID-19 hospitalization, critical care, and mortality in China and Italy. But among the more diverse patient population in New York, Dr. Alemán says, another observation soon crystallized: a body mass index (BMI) greater than 30 was likely putting younger patients at higher risk as well. Even more troubling, he and colleagues began diagnosing new-onset diabetes among multiple patients with COVID-19 and obesity.

Multiple research groups at NYU Langone, including a team led by Leora Horwitz, MD, associate professor of medicine and of population health, and another led by Jennifer L. Lighter, MD, associate professor of pediatrics, and Michael S. Phillips, MD, chief hospital epidemiologist, raced to study the worrisome anecdotal reports. In a major retrospective study of 6,585 patients treated for COVID-19 throughout the national VA healthcare system, Dr. Alemán and colleagues confirmed age as a primary risk factor for poorer outcomes and reaffirmed the previous studies’ findings of male sex and obesity as important additional factors. By combing through the extensive medical records of veterans seeking care in the VA system, though, Dr. Alemán’s group discovered another major and previously undocumented risk factor.

“In the veteran population, poor glycemic control, as measured by hemoglobin A1c levels, is a stronger risk factor for poor COVID-19 outcomes than BMI when compared head-to-head,” he says. His group’s data, in fact, suggest that a high hemoglobin A1c count is three- to fourfold more predictive than high BMI at all outcome levels. Together, the two factors seem to have a synergistic effect. “We’re in the process of establishing just how much it is, but it’s more than an additive effect,” Dr. Alemán says.

Overlapping Epidemics

The obesity epidemic in the United States, decades in the making and driven in part by a lack of access to both nutritious food and good healthcare, he says, has disproportionately affected underserved Black and Hispanic communities. “So we have a long-standing epidemic that is overlapping with a new pandemic that has been dubbed, ‘The Great Revealer,’” Dr. Alemán says. In particular, underserved minority communities may be less healthy at baseline and thus more susceptible to COVID-19 than their white counterparts. “A large segment of our population is a lot sicker than they think, by virtue of their underlying excess weight and the associated complications that have not been investigated, and COVID-19 laid that bare,” Dr. Alemán says.

Precisely how obesity and glycemic control may be exacerbating the risk is still unknown. More than a decade ago, though, researchers discovered that in patients with obesity, about 70 percent have an excess number of macrophage cells in their adipose tissue. Macrophages, charged mainly with clearing infections and cellular debris, play a critical role in regulating inflammation. Dr. Alemán and other researchers began viewing obesity as a chronic inflammatory state, and hypothesized that the inflammation starts in dysfunctional adipose tissue for unknown reasons and propagates to the circulatory system. Researchers observed that patients with obesity have increased levels of circulating inflammatory markers, and Dr. Alemán is investigating to what degree this low-grade inflammation might be reversible.

In a 2017 clinical weight loss study of postmenopausal women with obesity who were put on a low-calorie diet, his group found that the patients’ insulin, glucose, leptin, and inflammation marker levels all improved. Unexpectedly, however, the researchers saw increased macrophage infiltration of the patients’ adipose tissue during the early phase of weight loss.

Animal studies from other labs have suggested that such infiltration is transient during continued weight loss, but Dr. Alemán hypothesizes that it represents a significant risk factor for complications of obesity. Based on his continued research and clinical work, he believes doctors might be able to treat inflammation separately from achieving weight loss in patients with chronic obesity. “That means we might possibly mitigate some of complications of excess weight that we think are related to inflammation—like diabetes, cardiovascular disease, and now COVID-19,” he says.

Investigating the Consequences of Inflammation

By measuring systemic inflammatory markers, Dr. Alemán and colleagues hope to understand whether patients with obesity and dysfunctional adipose tissue are less protected by any forthcoming COVID-19 vaccine. If so, the research may help identify patients who are at high risk for a poorer prognosis and less likely to benefit from standard vaccine administration.

Therapeutic trials may help provide additional answers. Although initial trials testing an inhibitor of the pro-inflammatory cytokine IL-6 have not suggested a clear benefit for critically ill patients with COVID-19, trials with the corticosteroid medication dexamethasone have yielded more promising results. “That lends credence to the idea that curbing the widespread inflammation, which is what steroids do, might have benefits,” Dr. Alemán says.

To further tease out the potential links, he hopes to compare the metabolic and inflammatory changes in patients with diabetes who undergo bariatric surgery with their counterparts without diabetes and patients diagnosed with COVID-19. Although many questions remain unresolved, the emerging links among COVID-19, obesity, and glycemic control support the idea that obesity represents multiple diseases and that a specific type characterized by dysfunctional adipose tissue and inflammation may lead to more severe COVID-19 complications.