- Design
- Secondary analysis of two randomised, placebo-controlled, double-blind crossover trials
- Population
- 123 adults with type 2 diabetes (empagliflozin 69, dapagliflozin 54)
- Primary outcome
- Plasma TMAO and its renal clearance
- Effect
- Plasma TMAO +11.5% vs placebo (p=0.006); renal clearance −10.3% (p=0.048)
This analysis used stored samples from two randomised, placebo-controlled crossover trials of empagliflozin (69 people) and dapagliflozin (54) in type 2 diabetes. It measured trimethylamine-N-oxide (TMAO), a gut-derived metabolite linked in observational studies to cardiovascular risk, in plasma and 24-hour urine.
Across 123 people, plasma TMAO was 11.5% higher on an SGLT2 inhibitor than on placebo, and its renal clearance 10.3% lower, without change in urinary excretion. The effect was larger with dapagliflozin (23.4% higher plasma level); empagliflozin showed the same direction without reaching significance.
This matters only as a puzzle: SGLT2 inhibitors reduce cardiovascular and kidney events in large outcome trials, so a rise in a supposed risk marker does not outweigh that evidence. It may indicate that TMAO is a weaker causal marker than thought, or a renal handling effect. It is no reason to change prescribing.
- Continue SGLT2 inhibitors where indicated; outcome trials outweigh a biomarker shift.
- Do not measure TMAO in routine practice.
- Recognise that SGLT2 inhibitors alter renal handling of several solutes.
- Treat this as a research question, not a safety signal.
Why it matters
Biomarker scares can undermine confidence in drugs with proven outcome benefit.
Don't overread it
A surrogate biomarker; it says nothing about clinical events.
The statistics, in plain English
An 11.5% rise in a biomarker is small and its clinical significance is unknown. The dapagliflozin-only analysis is a subgroup of 54 people, which is less reliable than the pooled result.
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