Cardiovascular Benefits of Empagliflozin Are Associated With Gut Microbiota and Plasma Metabolites in Type 2 Diabetes

Abstract

Context Cardiovascular benefits of empagliflozin in patients with type 2 diabetes mellitus (T2DM) have been reported; however, the underlying mechanism remains unknown. Objective We hypothesized that the cardiovascular benefits of empagliflozin are associated with altered gut microbiota and plasma metabolites, and that empagliflozin may be used as an initial treatment for patients with T2DM at risk of cardiovascular diseases (CVDs). Design Randomized, open-label, two-arm clinical trial for 3 months. Setting Hospital. Patients Seventy-six treatment-naïve patients with T2DM and risk factors for CVD. Intervention Treatment with empagliflozin (10 mg/d, n = 40) or metformin (1,700 mg/d, n = 36). Main Outcome Measures We investigated changes in clinical parameters related to glucose metabolism and CVD risk factors, gut microbiota using 16S rRNA gene sequencing, and plasma metabolites using LC-MS. Results We found significant and similar reduction in HbA1c levels and alleviation of glucose metabolism in both groups. However, only empagliflozin improved CVD risk factors. Empagliflozin significantly reshaped the gut microbiota after 1 month of treatment; this alteration was maintained until the end of the trial. Empagliflozin increased the levels of plasma metabolites such as sphingomyelin, but reduced glycochenodeoxycholate, cis-aconitate, and uric acid levels. Concurrently, empagliflozin elevated levels of short-chain fatty acid-producing bacteria such as species from Roseburia, Eubacterium, and Faecalibacterium, and reduced those of several harmful bacteria including Escherichia-Shigella, Bilophila, and Hungatella. Conclusions Empagliflozin may be a superior initial therapy for patients with T2DM at risk of CVDs; its cardiovascular benefits may be associated with shifts in gut microbiota and plasma metabolites.

A systematic review and meta-analysis of gut microbiota in diabetic kidney disease: Comparisons with diabetes mellitus, non-diabetic kidney disease, and healthy individuals

“…The genera Hungatella, Bilophila, and Escherichia are all gram-negative, recognized by their pathogenic and infectious potential, since many members are opportunistic pathogens that induce inflammation and disrupt gut barrier function (39)(40)(41). Interestingly, patients with type 2 diabetes receiving empagliflozin showed similar gut microbiota alterations with our findings, accompanying with improved glucose metabolism and decreased interleukin-6 (IL-6), that is, depleted taxa of the harmful bacteria of Escherichia, Bilophila, and Hungatella, and enrichment of SCFA-producing bacteria, such as Roseburia and Faecalibacterium (42). Hungatella was reported as a TMAO-producer (41), whereas Bilophila is a sulfate-reducing bacteria, which have pro-inflammatory effects and have been shown to be associated with a variety of inflammatory or immune diseases, such as diabetes and metabolic syndrome (43).…”

Effects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites

“…However, the results were inconsistent, and dapagliflozin treatment was found to have no beneficial effects on gut bacteria in diabetic rats ( 112 ). Only two clinical studies explored the alteration of fecal microbiome with SGLT2 inhibitor treatment ( 87 , 88 ). Seventy-six treatment-naive T2DM with risk factors for CVD were included in a randomized, open-label, two-arm clinical trial ( 88 ).…”

“…Only two clinical studies explored the alteration of fecal microbiome with SGLT2 inhibitor treatment ( 87 , 88 ). Seventy-six treatment-naive T2DM with risk factors for CVD were included in a randomized, open-label, two-arm clinical trial ( 88 ). After a 3-month intervention, empagliflozin improved glucose metabolism and reduced CVD-related risks, while it significantly altered the gut microbiota, including an increase in SCFA-producing bacteria and a reduction in several harmful bacteria such as Escherichia–Shigella , Bilophila , and Hungatella ( 88 ).…”

“…Seventy-six treatment-naive T2DM with risk factors for CVD were included in a randomized, open-label, two-arm clinical trial ( 88 ). After a 3-month intervention, empagliflozin improved glucose metabolism and reduced CVD-related risks, while it significantly altered the gut microbiota, including an increase in SCFA-producing bacteria and a reduction in several harmful bacteria such as Escherichia–Shigella , Bilophila , and Hungatella ( 88 ). However, another clinical study found no significant effect on microbial alpha diversity or composition ( 87 ).…”

Changes in the composition of gut and vaginal microbiota in patients with postmenopausal osteoporosis

“…Genomic DNA was extracted from feces and vaginal swabs using a QIAamp PowerFecal Pro DNA Kit (51804; QIAGEN, Germantown, MD, USA), as in our previous study (27,28). The composition of the bacterial community in fecal samples was characterized via 16S rRNA gene amplicon sequencing.…”