GLP-1 and Kidney Disease: The FLOW Trial and What It Means for CKD Patients

3,533 patients, 28 countries, and a trial that ended ahead of schedule

Kidney disease rarely makes headlines. It progresses quietly, often for years, before anyone notices. But when an independent data monitoring committee stops a clinical trial early because the drug is working too well to keep giving some patients a placebo, that tends to get people's attention.

That is what happened with the FLOW trial, the first large-scale randomized controlled trial designed specifically to test whether a GLP-1 receptor agonist could slow kidney disease progression. Previous GLP-1 trials had measured cardiovascular outcomes with kidney data collected as secondary endpoints. FLOW flipped that, making kidney disease events the primary outcome.

Led by Dr. Vlado Perkovic at the University of New South Wales in Australia, the trial enrolled 3,533 patients from 387 sites across 28 countries. Every participant had both type 2 diabetes and chronic kidney disease. They were randomly assigned to receive either once-weekly subcutaneous semaglutide (the active ingredient in Ozempic) at 1.0 mg or a matching placebo.

The inclusion criteria targeted patients with real kidney damage, not mild risk factors. Eligible participants needed an estimated glomerular filtration rate (eGFR) between 25 and 75 ml/min/1.73 m2 combined with significant albuminuria, and all had to be on a stable dose of an ACE inhibitor or ARB, the existing standard of care for kidney protection. Think of eGFR as a speedometer for your kidneys: a healthy reading sits above 90, and below 60 means your kidneys are losing ground. The patients in this trial averaged an eGFR of 47, meaning most had stage 3 CKD or worse.

The dosing followed an 8-week escalation schedule, starting at 0.25 mg weekly for four weeks, then 0.5 mg for another four weeks, before reaching the maintenance dose of 1.0 mg per week. This ramp-up mirrors the standard dosing protocol for Ozempic in diabetes and exists mainly to reduce gastrointestinal side effects.

The trial was designed to run for five years. It lasted 3.4 years before the data monitoring committee called it, citing overwhelming evidence of benefit at a prespecified interim analysis. That early termination is, paradoxically, one of the strongest signals a trial can produce.

A 24% reduction in kidney disease progression and the mortality data nobody expected

The primary endpoint was a composite of major kidney disease events: onset of kidney failure (meaning dialysis, transplantation, or eGFR dropping below 15), a sustained 50% or greater reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. This is a hard endpoint. It measures things that actually change a patient's life, not just laboratory numbers.

Semaglutide reduced the risk of this primary composite by 24% compared to placebo (hazard ratio 0.76; 95% CI 0.66-0.88; P = 0.0003). In raw numbers, 18.7% of semaglutide patients experienced a primary event versus 23.2% on placebo.

The kidney-specific components alone showed a 21% reduction (HR 0.79; 95% CI 0.66-0.94), confirming this was not just a cardiovascular mortality effect in disguise.

But the secondary outcomes are where this trial separated itself from anything that came before it in CKD treatment. Death from cardiovascular causes dropped 29% (HR 0.71; 95% CI 0.56-0.89). Major cardiovascular events (heart attacks, strokes, and CV death combined) fell 18% (HR 0.82; 95% CI 0.68-0.98; P = 0.029). All-cause mortality dropped 20% (HR 0.80; 95% CI 0.67-0.95; P = 0.01).

At 156 weeks (about 3 years), the number needed to treat (NNT) to prevent one death was 39. For context, that means if 39 patients took semaglutide instead of placebo for three years, one additional person would be alive who otherwise would not have been.

Dr. Muthiah Vaduganathan, a cardiologist at Brigham and Women's Hospital, put the mortality finding in perspective: "This is really one of the first trials that has shown convincing mortality benefits with any therapy in a target population of CKD and type 2 diabetes."

The eGFR slope data tells a more granular story about what was happening to these patients' kidneys over time. Semaglutide slowed the annual rate of kidney function decline by 1.16 ml/min/1.73 m2 per year compared to placebo (P < 0.001). That may sound modest as an annual number, but kidney decline compounds. Over a decade, that difference represents substantial preserved function, potentially years before someone needs dialysis.

Outcome	Semaglutide	Placebo	Hazard Ratio (95% CI)
Primary composite (kidney events + CV/kidney death)	18.7%	23.2%	0.76 (0.66-0.88)
Kidney-specific composite	--	--	0.79 (0.66-0.94)
Cardiovascular death	7.0%	9.6%	0.71 (0.56-0.89)
Major cardiovascular events	--	--	0.82 (0.68-0.98)
All-cause death	12.8%	15.8%	0.80 (0.67-0.95)

Your kidneys have GLP-1 receptors, and that changes the whole story

When semaglutide was first developed, nobody was thinking about kidneys. The drug mimics a gut hormone called glucagon-like peptide-1 that your small intestine releases after meals. It signals the pancreas to produce insulin, tells the liver to slow glucose release, slows stomach emptying, and tells the brain you are full. That is how it lowers blood sugar and causes weight loss.

So why would a gut hormone drug protect kidneys? Because researchers discovered that GLP-1 receptors are present directly on kidney tissue, specifically in the proximal tubular cells and the smooth muscle cells of the blood vessels feeding the glomeruli (the kidney's filtering units). The kidneys are not bystanders in this process. They are active participants.

Think of it like discovering that a key you thought only opened the front door also fits the locks in the garage and the basement. The drug was built for one set of locks (blood sugar), but it turns out the kidneys have their own set.

The direct kidney effects include several pathways. GLP-1 receptor agonists inhibit the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubules, which promotes sodium excretion. This natriuretic effect partly explains why these drugs lower blood pressure, and lower blood pressure means less mechanical stress on the kidney's fragile filtering structures.

They also reduce activation of the renin-angiotensin-aldosterone system (RAAS) within the kidney itself, including lowering angiotensin II levels. Since overactivation of the intrarenal RAAS is one of the primary drivers of diabetic kidney damage, this is a meaningful protective mechanism.

On the anti-inflammatory side, GLP-1 receptor activation triggers the cAMP-PKA signaling pathway, which has antioxidant effects that reduce the oxidative stress damage that diabetes inflicts on kidney tissue.

Then there are the indirect effects that any competent internist would predict: better blood sugar control, lower blood pressure, and weight loss. In FLOW, semaglutide patients lost an average of 5.55 kg compared to 1.45 kg in the placebo group over 104 weeks. Their HbA1c dropped by 0.87 percentage points versus 0.06 for placebo.

Here is what makes this interesting, though: the investigators specifically checked whether the kidney benefits could be explained by weight loss alone. They compared eGFR measurements using both creatinine-based and cystatin C-based calculations and found nearly identical results, ruling out the possibility that weight-loss-related drops in creatinine were creating an illusion of kidney protection. Dr. Vaduganathan at Brigham and Women's concluded that the findings "substantiate the hypothesis that GLP-1 receptor agonists in this target population have effects on disease progression that go well beyond just weight loss."

37 million Americans have CKD, but the FLOW data applies to a specific subset

According to the CDC's most recent data, approximately 37 million American adults (14% of the adult population) have chronic kidney disease. The overlap with diabetes is enormous: 41% of adults with type 2 diabetes also have CKD. And 87% of people with CKD do not know they have it, because early-stage kidney disease produces no symptoms.

FLOW specifically enrolled patients with type 2 diabetes plus moderate-to-severe CKD already on ACE inhibitors or ARBs. The typical participant was 66 years old, had a BMI of 32, and an eGFR of 47. If you have type 2 diabetes and your nephrologist has told you that your kidney function is declining, you are the person this trial was designed to help.

The treatment benefit was consistent across CKD severity categories, meaning patients with worse kidney function at baseline benefited just as much as those with milder disease (p for interaction > 0.05 across all subgroups).

One important caveat involves patients already taking SGLT2 inhibitors (drugs like empagliflozin and dapagliflozin that also protect kidneys). Only 15.6% of FLOW participants were on an SGLT2 inhibitor at baseline. Among those 550 patients, the primary endpoint showed no statistically significant benefit from adding semaglutide (HR 1.07; 95% CI 0.69-1.67), while patients not on SGLT2 inhibitors saw a clear 27% reduction (HR 0.73; 95% CI 0.63-0.85). The interaction test was not statistically significant (P = 0.109), and the subgroup was too small to draw firm conclusions. But the signal deserves attention. Whether semaglutide adds meaningful kidney protection on top of an SGLT2 inhibitor remains an open question that future trials will need to answer.

Another gap is race. Only 4.5% of FLOW participants were Black, despite the fact that CKD is significantly more common in Black adults (22%) than White adults (13%), and Black Americans are more than four times more likely to progress to end-stage kidney disease. The trial was not powered to detect differences across racial subgroups. Whether the benefits hold equally across all populations is unknown.

What about people with CKD who do not have diabetes? The FLOW trial cannot answer that question directly, but data from the SELECT trial offers a clue. In that separate study of over 17,000 obese patients without diabetes, semaglutide at 2.4 mg weekly reduced a composite kidney endpoint by 22% (HR 0.78; P = 0.02). The kidney benefit was even more pronounced in patients whose eGFR was already below 60 at baseline, with a 2.19 ml/min/1.73 m2 benefit at 104 weeks. Dedicated trials in non-diabetic CKD are now underway.

Subgroup	Sample Size	Primary Outcome HR	Statistically Significant?
All FLOW participants	3,533	0.76 (0.66-0.88)	Yes (P = 0.0003)
Without baseline SGLT2i	2,983	0.73 (0.63-0.85)	Yes (P < 0.001)
With baseline SGLT2i	550	1.07 (0.69-1.67)	No (P = 0.755)
SELECT (obese, no diabetes)	17,604	0.78 (0.63-0.96)	Yes (P = 0.02)

January 2025: Ozempic officially becomes a kidney drug

On January 28, 2025, the FDA approved Ozempic for use in people with type 2 diabetes and chronic kidney disease, expanding the drug's label to include reducing the risk of kidney disease progression, kidney failure, and cardiovascular death in this population. European regulators had already expanded the label in December 2024.

This matters because before FLOW, the toolkit for slowing diabetic kidney disease had three main components: ACE inhibitors or ARBs (which have been around since the 1990s), SGLT2 inhibitors (proven for kidney protection in the DAPA-CKD and CREDENCE trials), and finerenone (a nonsteroidal mineralocorticoid receptor antagonist approved based on the FIDELIO and FIGARO trials). Semaglutide now becomes what Dr. Vaduganathan called the "fourth foundational pillar" of care for this population.

The financial stakes are real. Medicare spent nearly $77 billion on beneficiaries with CKD in 2021, and the average annual cost for a Medicare beneficiary with CKD was $28,162, more than double the $13,604 for those without kidney disease. If semaglutide delays progression to dialysis for even a fraction of these patients, the downstream cost savings could be substantial.

Dr. Darren McGuire at UT Southwestern called FLOW's results "paradigm shifting" but added a caveat that matters to patients right now: the medication needs to be accessible, with third-party payor coverage, and Novo Nordisk needs to produce enough supply, which he described as "the rate-limiting step across all injectable semaglutide indications."

For patients navigating the health system, the practical implications of this label expansion are straightforward. Previously, prescribing Ozempic for a CKD patient required justifying it as a diabetes drug that happened to help kidneys. Now there is an FDA-approved indication specifically for kidney protection in type 2 diabetes with CKD, which strengthens the case for insurance coverage. If you have been prescribed semaglutide and your insurer denied it, the new indication gives your doctor stronger ground for an appeal. For more on what to know about semaglutide safety, see our guide to Ozempic safety and semaglutide side effects.

The practical conversation every CKD patient should be having

The National Kidney Foundation's current guidance recommends considering a long-acting GLP-1 receptor agonist for adults with type 2 diabetes and CKD who have not reached their diabetes goals on metformin plus an SGLT2 inhibitor. In other words, semaglutide is not a first-line kidney drug. It slots in after the existing standard therapies are already on board.

The safety profile in FLOW was reassuring overall. Serious adverse events were actually lower in the semaglutide group (49.6%) than in the placebo group (53.8%), driven by fewer serious infections and cardiovascular events. The main downside was gastrointestinal: nausea, vomiting, and diarrhea led to more permanent discontinuations in the semaglutide group. The dose escalation from 0.25 mg upward exists specifically to minimize these effects, and eating smaller meals more slowly helps considerably. For a broader overview of GLP-1 drug safety considerations, see our GLP-1 weight loss drugs safety guide.

Access remains a barrier. The National Kidney Foundation identifies three main hurdles: step therapy requirements (insurers may require trying cheaper drugs first), high out-of-pocket costs at the pharmacy, and Medicare and Medicaid coverage gaps. The Department of Health and Human Services has announced plans to negotiate GLP-1 RA prices for Medicare patients, but the timeline for those negotiations to translate into lower pharmacy prices is unclear.

If you have type 2 diabetes and CKD, or if you have diabetes and have never had your kidney function checked (you are likely in the 87% of CKD patients who do not know they have it), here is what to bring up with your doctor:

• Ask for a basic kidney panel: eGFR and urine albumin-to-creatinine ratio. These two tests can identify CKD that you cannot feel.
• If you already have CKD, ask whether you are on the standard therapies (ACEi/ARB, SGLT2 inhibitor) before discussing adding semaglutide.
• If you are already on an SGLT2 inhibitor, discuss the open questions about whether semaglutide adds kidney protection on top of that.
• Ask about the dose escalation schedule and strategies for managing GI side effects if semaglutide is prescribed.
• Check your insurance coverage before filling the prescription. Ask your doctor's office about prior authorization requirements and manufacturer patient assistance programs.

Frequently Asked Questions

Does semaglutide work for kidney disease in people who do not have diabetes?

The FLOW trial only included patients with type 2 diabetes, so it cannot directly answer this. However, the SELECT trial showed a 22% reduction in a composite kidney endpoint in obese patients without diabetes taking semaglutide 2.4 mg weekly. Dedicated trials in non-diabetic CKD are ongoing, but no FDA approval exists for this use yet.

Can I take semaglutide if I am already on an SGLT2 inhibitor like empagliflozin or dapagliflozin?

Yes, there is no contraindication to combining them. In the FLOW trial, about 15.6% of participants were on an SGLT2 inhibitor at baseline. The cardiovascular and mortality benefits of semaglutide appeared similar regardless of SGLT2 inhibitor use. The kidney-specific benefit was less clear in the combination subgroup, though the analysis was underpowered. Your doctor can help weigh the potential benefits against the added cost and pill burden.

How long do I need to take semaglutide to see kidney benefits?

The FLOW trial measured outcomes over a median of 3.4 years. The eGFR slope differences were measured at 104 weeks (about 2 years). This is a long-term therapy, not a short course. Kidney disease progresses slowly, and the benefits of semaglutide accrue over time. Stopping the drug would likely mean losing the ongoing protection.

What are the most common side effects of semaglutide in CKD patients?

Nausea, vomiting, diarrhea, and constipation are the most reported side effects, mostly related to slowed gastric emptying. These tend to improve over time and are minimized by the dose escalation protocol. Importantly, the overall rate of serious adverse events was actually lower in the semaglutide group (49.6%) than the placebo group (53.8%).

Will my insurance cover Ozempic for kidney disease?

Coverage varies by insurer. The January 2025 FDA approval for CKD in type 2 diabetes strengthens the case for coverage, but barriers remain including step therapy requirements and high copays. Ask your doctor's office to check prior authorization requirements before filling the prescription.