Endocrinol Diabetes Metab. 2026 Nov;9(6):e70318. doi: 10.1002/edm2.70318.
ABSTRACT
BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have become a key drug class in the treatment of Type 2 diabetes (T2D) due to their effectiveness in blood sugar control, but also for many other clinical indications because of beneficial effects on cardiovascular diseases and mortality. Therefore, the findings of a secondary analysis of the recent EMMY trial, in which acute myocardial infarction patients treated with empagliflozin had higher trimethylamine-N-oxide (TMAO) serum levels compared to placebo, were unexpected, as high TMAO concentrations in blood have previously been linked to adverse cardiovascular and mortality outcomes. In light of this, the aim of our study was to explore the effects of the SGLT-2 inhibitors empagliflozin and dapagliflozin on plasma concentrations and renal clearance (ClR) in a T2D patient setting.
METHODS: Plasma and 24-h urine samples from two prospective, randomised, placebo-controlled, double-blind, cross-over trials with T2D patients (empagliflozin N = 69, NCT02471963; dapagliflozin N = 54, NCT02383238), taken at baseline and after each treatment with either SGLT-2 inhibitor or placebo, were measured for TMAO via LC-MS/MS.
RESULTS: After treatment with an SGLT-2 inhibitor, in the total of 123 patients, TMAO plasma levels were 11.5% higher compared to placebo (p = 0.006) and ClR of TMAO was reduced by 10.3% (p = 0.048) without any relevant change in its urinary excretion (p = 0.521). In the dapagliflozin trial, TMAO plasma concentration was 23.4% higher (p = 0.021), and ClR of TMAO was 22.6% lower (p = 0.025) after treatment with dapagliflozin compared to placebo. For empagliflozin, a similar trend was observed, but did not reach statistical significance.
CONCLUSION: Treatment with an SGLT-2 inhibitor was associated with a modest increase in plasma concentration of TMAO. Together with data from a previous trial, the present findings suggest a possible class effect of SGLT-2 inhibitors. Whether this effect impacts the overall clinical benefits of SGLT-2 inhibitors needs to be subject to further investigations.
TRIAL REGISTRATION: http://www.
CLINICALTRIALS: gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.
PMID:42817074 | DOI:10.1002/edm2.70318