'Profound Implications': COVID Ups Diabetes Risk 40% a Year Later

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COVID-19 infection appears to significantly raise the risk for diabetes by about 40% at 1 year, indicate new data from a very large Veterans Administration population.

"If patients have a prior history of COVID-19, that's a risk factor for diabetes and they should certainly be screened for diabetes," study co-author Ziyad Al-Aly, MD, a nephrologist and chief of research and development at VA St Louis Health Care, Missouri, told Medscape Medical News.

"It's still premature to make guidelines. I think we have to process the data landscape to understand what this all really means, but it's really, really clear that all these roads are pointing in one direction, that COVID-19 increases the risk of diabetes up to a year later. The risk is small but not negligible," he said.

The database includes over 8 million people and 180,000 with a prior COVID-19 diagnosis. Significantly increased diabetes risks compared to those not infected ranging from 31% to more than double were found in a subgroup analysis based on diabetes risk score, body mass index, age, race, prediabetes status, and deprivation level, and even after adjusting for confounding factors.

There was a gradient of diabetes risk by COVID-19 severity — ie, whether patients had not been hospitalized, had been hospitalized, or stayed in intensive care — but a significant excess diabetes burden was seen even among those with "mild" COVID-19. Diabetes risk was also elevated compared with contemporary and historical controls.

The study was published March 21 in The Lancet Diabetes & Endocrinology by Yan Xie, MPH, also of VA St Louis Health Care, along with Al-Aly.

The data align with those from another study just published from a nationwide German primary care database. That study was smaller and of shorter duration than the new VA study but consistent, said Al-Aly, who is also a clinical epidemiologist at the Washington University School of Medicine, St Louis, Missouri.

Millions More With New Diabetes as Late Manifestation of COVID-19

"Millions of people in the US have had COVID-19, so this is going to translate to literally millions of more people with new-onset diabetes. Better to identify them early so they can be adequately treated," Al-Aly told Medscape Medical News.

"The long-term implications of SARS-CoV-2 infection increasing diabetes risk are profound," said Venkat Narayan, MD, and Lisa R. Staimez, PhD, both of the Rollins School of Public Health and Emory Global Diabetes Research Center at Emory University, Atlanta, in an accompanying editorial.

"With large and growing numbers of people worldwide infected with SARS-CoV-2 (434,154,739 cumulative cases by February 28, 2022), any COVID-19–related increases in diabetes incidence could lead to unprecedented cases of diabetes worldwide — wreaking havoc on already over-stretched and under-resourced clinical and public health systems globally, with devastating tolls in terms of deaths and suffering," they add.

Medscape Medical News contributor Eric Topol, MD, of Scripps Research Institute, La Jolla, California, agrees. He also said these new data "are most profound. The researchers found a 40% increase in diabetes that wasn't present at 1 month after COVID-19 — but at 1 year, it was. Some kind of late manifestation is happening here."

Al-Aly told Medscape Medical News that the mechanisms for the association are unknown and likely to be heterogeneous. Among the people who already had risk factors for type 2 diabetes, such as obesity or metabolic syndrome, SARS-CoV-2 could simply accelerate that process and "put them over the edge" to overt diabetes.

However, for those without diabetes risk factors, "COVID-19 with all the inflammation it provokes in the body could be leading to de novo disease." (Diabetes status was ascertained by ICD-10 codes and only about 0.70% of the total were recorded as type 1 diabetes. But, because autoantibody testing wasn't routinely conducted, it's unknown how many of the cases may have been type 1 diabetes misclassified as type 2 diabetes, Al-Aly acknowledged.)

Diabetes Risk Significantly Increased After COVID-19 in All Analyses

The analysis included 181,280 individuals in the US Department of Veterans Affairs healthcare database with a COVID-19 diagnosis and who survived for at least 30 days afterward from March 2020 through September 30, 2021, with 4,118,441 contemporary controls without COVID-19 seen during 2019, and a historical control group of 4,286,911 people seen at the VA in 2017. Average follow-up was about a year.

Compared with the contemporary controls, the COVID-19 group had an excess diabetes burden of 13.46 per 1000 person-years, with a hazard ratio of 1.40. They also had an increased risk for incident use of glucose-lowering medications of 12.35 per 1000 person-year, with a hazard ratio of 1.85. Similar results were seen compared with historical controls.

Subgroup analyses showed an increased risk for diabetes following COVID-19 infection by age (≤ 65 years and > 65 years), race (White and Black), sex (male and female), BMI category (> 18.5 to ≤ 25 kg/m², > 25 to ≤ 30 kg/m², and > 30 kg/m²), and area deprivation index quartiles. The increased risk was also seen across diabetes risk score quartiles.

Notably, COVID-19 significantly elevated the diabetes risk by 59% even in the subgroup with a BMI between 18 and 25 kg/m², and by 38% among those with the lowest diabetes risk score quartile.

The COVID-19 population included 162,096 individuals who were not hospitalized, 15,078 hospitalized, and 4106 admitted to intensive care. Here, hazard ratios for diabetes compared with contemporary controls were 1.25, 2.73, and 3.76, respectively (all significant).

Al-Aly said that his group is further analyzing the VA data for other outcomes including cardiovascular disease and kidney disease, as well as now well-documented long COVID symptoms including fatigue, pain, and neurocognitive dysfunction.

The group is also investigating the impact of the COVID-19 vaccine to see whether the risks are mitigated in the case of breakthrough infections. "We're doing a broad systematic assessment. The next paper will be more comprehensive," Al-Aly said.

Narayan and Staimez write: "The potential connection between COVID-19 and diabetes highlights that infectious diseases (eg, SARS-CoV-2) and chronic diseases (eg, diabetes) cannot be viewed in siloes. When we emerge out of the pandemic, the much-neglected noncommunicable diseases, such as type 2 diabetes, will continue their relentless trajectory, possibly in an accelerated manner, as the leading burdens of global health."

Al-Aly has received support from the US Department of Veterans Affairs for the submitted work. He has reported receiving consultation fees from Gilead Sciences and funding (unrelated to this work) from Tonix Pharmaceuticals. He is a member of the board of directors for Veterans Research and Education Foundation of St Louis, associate editor for the Journal of the American Society of Nephrology, and is a member of multiple editorial boards. Narayan and Staimez have reported receiving support from the National Institutes of Health.

Lancet Diabetes Endocrinol. Published online March 21, 2022. Full text, Editorial

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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