Researchers discovered that a diabetes medication altered how certain immune cells function, potentially reducing harmful inflammation.
A medication already used to treat diabetes may protect the heart by changing how immune cells behave in the bloodstream. In a small human clinical trial, researchers found that the drug reduced inflammatory cell clusters associated with cardiovascular disease, with measurable effects appearing after just two weeks.
The findings, published in the American Heart Association journal Circulation, provide the first direct evidence that sodium-glucose cotransporter-2 (SGLT2) inhibitors can alter specific immune cells in humans. These medications are known for lowering blood sugar, promoting weight loss, and providing cardiovascular and kidney benefits, but their effects on inflammation have been less clear.
A Rapid Reduction in Inflammatory Blood Cells
Researchers at Vanderbilt Health studied 16 women with obesity and prediabetes who received the SGLT2 inhibitor empagliflozin for three months. Blood samples collected before treatment, after two weeks, and after 12 weeks allowed investigators to track changes in immune activity. The team also examined a separate comparison group of women who followed a low-calorie diet for three months.
Using advanced genetic sequencing and cellular imaging, the researchers identified a significant reduction in monocyte platelet aggregates (MPAs). These clusters form when blood-clotting cells (platelets) attach to immune cells (monocytes), creating structures associated with inflammation in blood vessels and cardiovascular disease.
MPA levels declined significantly within two weeks of starting empagliflozin and fell further by the end of the study. The women in the diet comparison group did not show the same reduction, suggesting that the medication’s effects on these cells may extend beyond its influence on body weight.
Diabetes Medication Changes Immune Cell Behavior
The researchers also identified evidence of “metabolic reprogramming” in monocytes (immune cells). These cells shifted away from a highly inflammatory state toward a more stable metabolic profile associated with normal cellular energy production.
“There had been some suggestive studies in animals with these medications indicating they might be modulating the immune system — affecting inflammation — but that hadn’t really been shown in humans,” said Mona Mashayekhi, MD, PhD, Assistant Professor of Medicine in the Division of Diabetes, Endocrinology and Metabolism at Vanderbilt Health.
“This study provides the first direct evidence of SGLT2 inhibitors altering human immune cells, which may potentially reduce cardiovascular risk.”
A Larger Trial Will Investigate the Mechanism
“This finding is significant because it’s the first time this medication has been shown to have an immune effect at the cellular level with some specificity. If we understand how these medicines are reducing obesity-associated inflammation and heart disease and kidney disease, then we can identify the best patient for this treatment or discover other drug targets in that pathway that could really be beneficial.”
Mashayekhi and her colleagues have launched a randomized, placebo-controlled trial at Vanderbilt Health that aims to enroll 74 participants with obesity and metabolic syndrome. The study will examine immune changes over three months and analyze adipose tissue (fat) to investigate how the medication affects inflammation within the body.
The larger trial will help determine whether the immune changes observed in the initial study can be confirmed under more rigorous conditions and clarify how SGLT2 inhibitors influence inflammation associated with metabolic disease.
Reference: “SGLT2 Inhibitor Empagliflozin Reduces Circulating Monocyte-Platelet Aggregates: A Pilot Study” by B. Ilkin Safa, Jared M. Oakes, Joshua D. Simmons, Hui Nian, Leslie A. Kirk, Anna C. Cassidy, Eric C. Olson, Zaid Hatem, Christian M. Warren, Matthew S. Gonzalez, Taneem Amin, Quanhu Sheng, Anveetha Matta, Lyndon Zhu, Walid Hairan, Sara E. Howard, C. Robb Flynn, Matthew T. Stier, Erin M. Wilfong, Jeffrey C. Rathmell, Katherine N. Cahill, Jonathan D. Brown, Joshua A. Beckman, Curtis L. Gabriel, Jane E. Freedman, J. Matthew Luther, Samuel S. Bailin, Celestine N. Wanjalla, John R. Koethe, Spyros A. Kalams and Mona Mashayekhi, NaN Invalid Date NaN, Circulation.
DOI: 10.1161/CIRCULATIONAHA.125.077432
The research was supported in part by the National Institutes of Health (NIH) (grants K23HL159351, T32HL094296, R01AI182159 and R01AI142095).
RNASeq and genotyping were performed at the Vanderbilt Technologies for Advanced Genomics Core. Microscopy imaging was performed using the Vanderbilt Cell Imaging Shared Resource. Flow Cytometry experiments were performed in the Vanderbilt Flow Cytometry Shared Resource. This work was also supported by the Advanced Technologies Core Laboratory of the NIH-funded Tennessee Center for AIDS Research (P30 AI110527).
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