FLOW Trial: A Plain-English Overview of What It Established

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At a glance

| Detail | Value | |---|---| | Trial name | FLOW (Evaluate Renal Function with Semaglutide Once Weekly) | | N | 3,533 | | Intervention | Semaglutide 1 mg subcutaneous, once weekly | | Comparator | Matching placebo, once weekly | | Duration | Median 3.4 years (stopped early for efficacy) | | Primary endpoint | Composite of onset of kidney failure, sustained ≥50% eGFR decline, sustained eGFR <15 mL/min/1.73 m², or death from kidney or cardiovascular causes | | Key result | HR 0.76 (95% CI 0.66, 0.88); 24% relative risk reduction (Perkovic et al., NEJM 2024) |

The Question FLOW Was Built to Answer

GLP-1 receptor agonists like semaglutide had shown kidney-related signals in earlier cardiovascular trials. Post hoc analyses from SUSTAIN-6 and PIONEER-6 suggested the drug might slow albumin loss. But post hoc signals are not proof. No one had run a trial where kidney disease progression was the thing the study was actually powered to detect.

FLOW was that trial. It asked a single, specific question: in people who already have type 2 diabetes and established chronic kidney disease (CKD), does adding semaglutide 1 mg per week slow the worsening of their kidneys compared with placebo?

The answer, published in the New England Journal of Medicine in 2024, was yes.

Who Got Into the Trial

Enrollment criteria matter because they define whose results you can generalize. FLOW recruited adults aged 18 or older with type 2 diabetes and CKD. The CKD had to be confirmed by two measures taken together:

  • An estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m²
  • A urine albumin-to-creatinine ratio (UACR) between 300 and 5 to 000 mg/g

That second criterion is important. A UACR above 300 mg/g means the kidneys are leaking substantial amounts of protein. These were not people with mild, early-stage kidney trouble. They had meaningful, measurable kidney damage already underway.

At baseline, the median eGFR was about 47 mL/min/1.73 m² and the median UACR was roughly 568 mg/g. Mean age was 66.6 years. About 70% of participants were already on a renin-angiotensin system (RAS) inhibitor, and roughly 15.6% were on an SGLT2 inhibitor. That last detail matters for clinical context, since SGLT2 inhibitors like dapagliflozin had already proven kidney benefits in the DAPA-CKD trial.

Participants were recruited across 28 countries at 431 sites.

What They Were Given and How

Randomization was 1:1. Half received semaglutide 1 mg subcutaneously once a week. Half received a visually identical placebo injection. Standard dose escalation was used: participants started at 0.25 mg for four weeks, moved to 0.5 mg for four weeks, then reached the target 1 mg dose.

All participants continued their usual medications, including blood pressure drugs, statins, and any SGLT2 inhibitors they were already on. The trial did not require anyone to start or stop background therapy.

The Primary Endpoint, Explained

Kidney trials use composite endpoints because individual kidney events (like reaching dialysis) are relatively rare even in high-risk populations, and a trial would need tens of thousands of people to detect differences in a single event type. The FLOW composite bundled four outcomes into one measure:

| Component | What it means in plain terms | |---|---| | Onset of kidney failure | Need for chronic dialysis or kidney transplant | | Sustained ≥50% eGFR decline from baseline | Kidney filtration drops by half and stays there | | Sustained eGFR <15 mL/min/1.73 m² | Kidneys functioning at <15% capacity, persistently | | Death from kidney or cardiovascular causes | Fatal outcome tied to either organ system |

The word "sustained" is doing real work here. A single low lab reading does not count. The decline had to be confirmed at a second visit at least 28 days later. This reduces false positives from acute illness or lab variability.

Cardiovascular death was included in the composite because kidney disease and heart disease are biologically intertwined. Over 50% of deaths in CKD patients are cardiovascular. Excluding those deaths would have understated the drug's total impact on survival in this population.

What the Trial Found

Primary composite

The primary endpoint occurred in 331 of 1,767 participants in the semaglutide group versus 410 of 1 to 766 in the placebo group. That translates to a hazard ratio of 0.76 (95% CI, 0.66 to 0.88; P = 0.0003), a 24% relative risk reduction.

Individual components

| Endpoint | Semaglutide (n/N) | Placebo (n/N) | HR (95% CI) | |---|---|---|---| | Kidney failure (dialysis/transplant) | 65/1,767 | 80/1,766 | 0.81 (0.58, 1.12) | | ≥50% sustained eGFR decline | 150/1,767 | 215/1,766 | 0.69 (0.56, 0.85) | | CV death | 80/1,767 | 106/1,766 | 0.71 (0.53, 0.96) | | Kidney-related death | 4/1,767 | 7/1,766 |, |

The strongest individual signal came from the sustained 50% eGFR decline component (HR 0.69). Cardiovascular death also favored semaglutide (HR 0.71). Kidney failure (dialysis or transplant) trended in the right direction but did not reach statistical significance on its own. This is expected given the trial was stopped early (see below), reducing the number of events that accumulated.

eGFR slope

The annual rate of eGFR decline, measured as the slope over time, was significantly slower in the semaglutide group. After an initial acute dip in eGFR (a hemodynamic effect also seen with SGLT2 inhibitors and RAS inhibitors), the chronic slope showed a meaningful separation. Semaglutide slowed the annual eGFR decline by approximately 1.16 mL/min/1.73 m² per year compared to placebo. Over three or more years, that adds up.

Albuminuria

UACR dropped by roughly 40% more in the semaglutide arm than in placebo by week 104. Reduced albumin leakage is considered a surrogate marker for kidney protection, and this magnitude of reduction is clinically meaningful.

All-cause mortality

All-cause death occurred in 5.8% of the semaglutide group versus 7.5% of the placebo group (HR 0.80 to 95% CI 0.64, 0.99). This is a secondary endpoint, not the primary outcome, so it should be interpreted with that caveat. But a 20% reduction in dying from any cause is a strong secondary signal.

Why the Trial Stopped Early

FLOW was originally planned for approximately 5 years. In October 2023, the independent data monitoring committee reviewed unblinded interim data and recommended stopping enrollment and follow-up because the primary endpoint had already crossed the prespecified efficacy boundary. Participants had been followed for a median of 3.4 years at that point.

Early stopping for efficacy means the treatment benefit was so statistically convincing that continuing would have been ethically questionable, as it would keep half the participants on placebo for a condition where the intervention was clearly working. However, early stopping also means the trial collected fewer total events than planned, which can overestimate treatment effects and leaves less data for subgroup analyses.

How FLOW Fits Alongside Other CKD Trials

Before FLOW, two drug classes had proven kidney-specific benefits in dedicated outcomes trials:

FLOW adds GLP-1 receptor agonists as a third class with a dedicated kidney outcome win. A practical question clinicians now face is whether these drugs stack. About 15.6% of FLOW participants were already on SGLT2 inhibitors, and semaglutide still showed benefit in that subgroup. But FLOW was not powered to prove additive benefit definitively. The KDIGO 2024 guidelines now reference GLP-1 receptor agonists as an option for kidney risk reduction in T2D + CKD.

Limitations the Authors Acknowledged

  1. Early stopping inflates effect sizes. Stopping at 3.4 years instead of 5 means fewer events and wider confidence intervals. The true long-term HR could be closer to 1.0 than the point estimate of 0.76.
  2. Low SGLT2i use at baseline. Only 15.6% were on SGLT2 inhibitors. In current practice, a much higher percentage of T2D + CKD patients are prescribed these drugs. Whether semaglutide provides the same magnitude of benefit on top of full SGLT2i therapy remains an open question.
  3. Specific population. All participants had T2D plus macroalbuminuria. The results do not automatically apply to CKD without diabetes or CKD without significant proteinuria.
  4. GI side effects. Nausea and vomiting occurred more often with semaglutide (about 15% vs. 7% for nausea). For patients already dealing with uremic symptoms and appetite loss from advanced CKD, tolerability is a real-world concern.
  5. No head-to-head comparison. FLOW tested semaglutide against placebo, not against an SGLT2 inhibitor or finerenone. Cross-trial comparisons are unreliable due to different populations, background therapies, and endpoint definitions.

What This Means for Practice

For clinicians treating patients with type 2 diabetes and CKD with significant albuminuria, FLOW provides direct evidence that semaglutide 1 mg weekly reduces kidney disease progression. The Ozempic prescribing label was updated following these results.

The practical sequence most guidelines now suggest: maximize RAS inhibition first, add an SGLT2 inhibitor (the most extensively studied class for CKD in T2D), then consider adding semaglutide or finerenone based on the individual patient's profile. For patients who cannot tolerate SGLT2 inhibitors, FLOW's data offers an alternative path with proven kidney outcomes.

FLOW does not answer whether semaglutide protects kidneys in people without diabetes or without albuminuria. Those remain open research questions.

Frequently asked questions

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References

  • Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024;391(2):109-121. PubMed
  • Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446. PubMed
  • Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. PubMed
  • Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. PubMed
  • KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. PubMed
  • Ozempic (semaglutide) Prescribing Information. U.S. Food and Drug Administration. FDA Label