Important practical question. The FLOW trial didn't report detailed body composition data, but we know from STEP trials that ~40% of weight lost on semaglutide is lean mass[4]. In the CKD population, where sarcopenia and protein-energy wasting are already concerns, this is a legitimate worry.
In FLOW, GI adverse events led to treatment discontinuation in about 7% of the semaglutide group vs 2% of placebo. That's consistent with other semaglutide trials. Importantly, there was no excess signal for acute kidney injury, which could theoretically result from dehydration due to GI side effects.
Practically, for CKD patients: slow titration, adequate hydration, dietary counseling about protein intake (0.8 g/kg/day per KDIGO), and monitoring of albumin and prealbumin are all important. The benefit almost certainly outweighs the risk in most patients, but it requires careful clinical management.
[4] Wilding JPH, et al. N Engl J Med. 2021;384(11):989-1002.
One more point about FLOW that deserves attention: the CV death benefit (HR 0.71) was actually more robust than the kidney-specific benefit. This is consistent with SELECT and SUSTAIN-6 — semaglutide seems to have a powerful CV protective effect that may be partly independent of its kidney effects.
The question for the field is whether we're looking at two separate indications (CV protection + kidney protection) or whether the kidney benefit is substantially mediated through cardiovascular and hemodynamic pathways. The mediation analysis from FLOW hasn't been published yet, but I suspect HbA1c reduction and weight loss together explain ~50% of the kidney benefit, with the remainder being direct effects.
Regardless of mechanism, the clinical bottom line is clear: if I have a patient with T2D and CKD who is not on a GLP-1 RA, I now need a good reason for why not. The burden of proof has shifted.
Agreed on all points. Let me just flag the ongoing SOUL trial (semaglutide CV outcomes in T2D) and COORDINATE trials, which will give us even more data on the cardiorenal axis[5]. FLOW is practice-changing for diabetic CKD, but the full picture of GLP-1 RA renal effects across the CKD spectrum is still emerging.
For the community: if you're a patient with T2D and CKD, please discuss FLOW with your nephrologist. If you're a clinician, note that the dose in FLOW was 1.0 mg (not 2.4 mg used for obesity). The kidney protective effects appear to be present at the diabetes-treatment dose.
[5] ClinicalTrials.gov Identifier: NCT03914326.
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