Summary: In this double-blind, placebo-controlled mechanistic RCT of 34 adults with type 2 diabetes and heart failure, ertugliflozin did NOT increase the primary outcome of proximal tubular natriuresis (fractional excretion of lithium) at 1 or 12 weeks. It did transiently raise 24-hour urinary sodium (+47.5 mmol/day, p=0.032) and urine volume at 1 week, and by week 12 reduced extracellular fluid, estimated plasma volume, and mean arterial pressure, consistent with a shift toward euvolaemia.
PICO Summary
| Element | Detail |
|---|---|
| Population | 34 adults with type 2 diabetes and heart failure; double-blind, placebo-controlled, parallel-group, multicentre randomised trial with physiologic measurements under clamped euglycaemia. |
| Intervention | Ertugliflozin (SGLT2 inhibitor) for 12 weeks; physiologic assessments at baseline, 1 week, and 12 weeks. |
| Comparison | Matching placebo (parallel-group allocation; total n=34 randomised across both arms). |
| Outcome | Primary outcome NEGATIVE: ertugliflozin did not increase fractional excretion of lithium (FELi) or total fractional sodium excretion at 1 or 12 weeks. Secondary findings: 24-h urinary sodium +47.5 ± 22.1 mmol/day (p=0.032) and increased urine volume (p=0.009) at 1 week, attenuated by week 12. Week 12: extracellular fluid -1.9 ± 0.8 L (p=0.01), estimated plasma volume -11.9 ± 13.9% (p=0.02), supine mean arterial pressure -6.6 ± 2.7 mmHg (p=0.02). No 95% CIs, absolute risk reduction, or NNT reported (mechanistic endpoints, not clinical events). |
Expert Commentary
This is a mechanistic, physiology-focused trial, and its primary outcome was null: ertugliflozin did not increase proximal tubular natriuresis as measured by fractional excretion of lithium, the prespecified primary endpoint. That negative result should anchor interpretation. The clinically interesting signal sits in the secondary endpoints, where a transient natriuresis and diuresis at one week gave way by week 12 to meaningful reductions in extracellular fluid, estimated plasma volume, and mean arterial pressure. Taken together, the data are most consistent with the drug nudging systemic volume toward euvolaemia through a mechanism other than sustained proximal tubular sodium loss, which is a plausible explanation for why SGLT2 inhibitors reduce worsening heart failure without behaving like conventional loop diuretics. The dominant limitation is size and scope: with only 34 participants and surrogate physiologic endpoints, this study is hypothesis-generating and was never powered for clinical outcomes, so it cannot establish efficacy. The wide confidence around the plasma volume estimate also signals fragility. Can I use this with my patients? Not directly; nothing here changes prescribing, because the trial measures mechanism rather than events, and the patients who benefit clinically are already defined by the large cardiovascular and heart-failure outcome trials. Read this paper to understand how SGLT2 inhibitors may work, not whether to start one. I would welcome a larger mechanistic cohort that pairs these volume markers with hard endpoints to confirm the euvolaemia hypothesis.
References
Lytvyn Y, Scholtes RA, Boorsma EM, Sridhar VS, Kugathasan L, Liu H, et al. Mechanistic evaluation of ertugliflozin in patients with type 2 diabetes and heart failure. Physiol Rep. 2025;13(7):e70275. doi:10.14814/phy2.70275
