FLOW trial: semaglutide renal outcomes — NEJM publication review

Absolutely practice-changing. But let me raise a methodological point that I think is under-discussed: FLOW enrolled patients with T2D. We do not yet have kidney outcome data for semaglutide in CKD without diabetes.

This matters because DAPA-CKD showed benefit in both diabetic and non-diabetic CKD, which expanded the indication dramatically. EMPA-KIDNEY similarly showed benefit regardless of diabetes status[3]. Until we have similar data for GLP-1 RAs, we're limited to the diabetic CKD population.

That said, within the diabetic CKD population, the question of sequencing is fascinating. We already give RAAS inhibitors + SGLT2i. Do we now add semaglutide as a third agent? The FLOW participants had ~55% on SGLT2i at baseline, and the benefit was consistent in that subgroup. That's a strong signal for additive benefit.

Nephrologist here. I want to focus on the acute eGFR dip that was observed with semaglutide in FLOW. There was an initial ~3-4 mL/min decline in eGFR in the semaglutide group in the first few weeks, which then recovered and was followed by a much slower long-term decline compared to placebo.

This pattern is strikingly similar to what we see with SGLT2 inhibitors and RAAS inhibitors — the initial hemodynamic dip followed by long-term nephroprotection. This is thought to reflect reduced intraglomerular pressure (tubuloglomerular feedback with SGLT2i, efferent arteriolar dilation with RAAS inhibitors).

The mechanism with GLP-1 RAs is less clear. Proposed explanations include:

• Reduced proximal tubular sodium reabsorption (similar to SGLT2i mechanism)
• Decreased renal plasma flow from natriuresis
• Anti-inflammatory effects reducing hyperfiltration

Understanding the mechanism matters because if it's additive to SGLT2i (different pathway), then combination therapy has a strong rationale. If it's overlapping, the incremental benefit might plateau.

Let me put the FLOW numbers in context against the other kidney outcome trials:

The SGLT2i trials generally show numerically greater kidney benefit, particularly DAPA-CKD. But direct cross-trial comparison is fraught — different populations, different baseline therapies, different definitions of the composite endpoint. FLOW also had a higher proportion of patients on SGLT2i at baseline, which could attenuate the observed effect.

The KDIGO 2024 guidelines now recommend both SGLT2i and GLP-1 RA for patients with T2D and CKD. We've gone from one pillar (RAAS blockade) to three pillars of kidney protection in the span of 5 years. That's extraordinary progress.

This is very encouraging. My nephrologist started me on semaglutide specifically because of my CKD (stage 3b, eGFR around 38, T2D). I'm already on losartan and dapagliflozin.

One concern: I had significant nausea with semaglutide that made it hard to maintain nutrition, which my doctor worried about because malnutrition is already a risk with advanced CKD. Did the FLOW trial report on nutritional outcomes or muscle mass changes?