For the first time in a human trial, a class of drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors, already known for their weight loss and glucose-lowering benefits, has been shown to also reduce inflammatory cells in the blood known to cause cardiovascular disease. The findings were published in Circulation, a journal of the American Heart Association.
“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.
“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.”
The research team enrolled 16 women with obesity and prediabetes and treated them with the SGLT2 inhibitor empagliflozin. They performed baseline testing, then gave study participants the medication for a total of three months. They also reviewed immune changes in a comparator cohort of women who went on a low-calorie diet for three months. They took measures at two weeks and then at three months.
Using advanced genetic sequencing and cellular imaging, investigators discovered a cell type thought to contribute to vascular inflammation and cardiovascular disease — monocyte platelet aggregates, or MPAs — was significantly decreased in the blood. MPAs are cell aggregates formed when blood-clotting cells (platelets) stick to immune cells (monocytes).
Individuals taking the drug saw a significant drop in these inflammatory cell clumps within just two weeks, and the reduction grew even stronger by week 12. Only the group receiving the medication had reduced MPAs, indicating the medication’s heart-protective benefits go beyond simple weight loss.
Beyond the reduction in MPAs, the investigators also documented “metabolic reprogramming” of the patients’ monocytes (immune cells). They shifted from a hyper-inflammatory state toward a healthier, more stable state focused on normal cellular energy.
Mashayekhi and her colleagues have already begun a randomized placebo-controlled trial, currently enrolling at Vanderbilt Health, with a planned cohort of 74 participants with obesity and metabolic syndrome. Changes in immune measures over three months will be analyzed as in the pilot study, but this time, adipose tissue (fat) will also be collected and analyzed to better understand obesity-associated inflammation.
The research was supported in part by the National Institutes of Health (NIH) (grants K23HL159351, T32HL094296, R01AI182159 and R01AI142095). A full list of funding support can be found in the Circulation paper.
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).
