Effects of SGLT-2 Inhibitors on Plasma Concentrations and Renal Clearance of the Risk Marker Trimethylamine-N-Oxide in Patients With Type-2 Diabetes

IF 2.6 Q3 ENDOCRINOLOGY & METABOLISM

Endocrinology, Diabetes and Metabolism Pub Date : 2026-09-30 DOI:10.1002/edm2.70318

Katja B. Zimmer, Arne Gessner, Dennis Kannenkeril, Agnes Bosch, Armin Ströbel, Roland E. Schmieder, Renke Maas

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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 (Cl_R) 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 Cl_R 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 Cl_R 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

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SGLT-2抑制剂对2型糖尿病患者危险标志物三甲胺- n -氧化物血浆浓度和肾脏清除率的影响

钠-葡萄糖共转运体-2 （SGLT-2）抑制剂由于其在血糖控制方面的有效性，已成为治疗2型糖尿病（T2D）的关键药物类别，但由于对心血管疾病和死亡率的有益作用，也可用于许多其他临床适应症。因此，在最近的EMMY试验中，与安慰剂相比，接受恩格列净治疗的急性心肌梗死患者血清中三甲胺- n -氧化物（TMAO）水平更高，这一结果的二次分析结果出乎意料，因为血液中高浓度的TMAO与不良的心血管和死亡率结果有关。鉴于此，我们研究的目的是探讨SGLT-2抑制剂恩格列净和达格列净对T2D患者血浆浓度和肾清除率（ClR）的影响。方法：通过LC-MS /MS检测两项前瞻性、随机、安慰剂对照、双盲、交叉试验T2D患者（恩格列净N = 69, NCT02471963；达格列净N = 54, NCT02383238）的血浆和24小时尿液样本，分别在基线和每次使用SGLT-2抑制剂或安慰剂治疗后采集TMAO。结果123例患者接受SGLT-2抑制剂治疗后，TMAO血浆水平较安慰剂升高11.5% (p = 0.006)， TMAO ClR降低10.3% (p = 0.048)，尿排泄无相关变化（p = 0.521）。在达格列净试验中，与安慰剂相比，达格列净治疗后TMAO血药浓度升高23.4% (p = 0.021)， TMAO ClR降低22.6% （p = 0.025）。恩格列净也有类似的趋势，但没有达到统计学意义。结论SGLT-2抑制剂治疗与血浆TMAO浓度适度升高相关。结合先前试验的数据，本研究结果提示SGLT-2抑制剂可能存在类效应。这种效应是否会影响SGLT-2抑制剂的总体临床获益还有待进一步研究。试验注册http://www.clinicaltrials.gov: NCT02471963（2015年6月15日注册，回顾性注册）和NCT02383238

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