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GLP-1 Agonists & Kidney Disease Research

For the roughly 40% of people with type 2 diabetes who also develop chronic kidney disease, treatment options have long been limited to a familiar trio: blood pressure drugs that block the renin-angiotensin system, SGLT2 inhibitors, and the mineralocorticoid receptor antagonist finerenone.

For the roughly 40% of people with type 2 diabetes who also develop chronic kidney disease, treatment options have long been limited to a familiar trio: blood pressure drugs that block the renin-angiotensin system, SGLT2 inhibitors, and the mineralocorticoid receptor antagonist finerenone. That changed in 2024, when the FLOW trial delivered the first definitive proof that a GLP-1 receptor agonist — semaglutide — can slow kidney disease progression in its own right. The trial was stopped early because the results were so clear.

This article breaks down the FLOW trial data, the earlier cardiovascular outcome trials that hinted at kidney benefits, the emerging evidence for tirzepatide, and what all of this means for people living with CKD and diabetes.

Table of Contents

  1. Why Kidneys and GLP-1 Receptors Are Connected
  2. The FLOW Trial: Semaglutide's Landmark Kidney Data
  3. Earlier Signals: LEADER, SUSTAIN-6, and REWIND
  4. SELECT Trial: Kidney Protection Without Diabetes
  5. Tirzepatide and Kidney Outcomes
  6. How GLP-1 Agonists Protect the Kidneys
  7. Meta-Analysis Data Across the GLP-1 Class
  8. FDA Approval and Clinical Practice
  9. What's Still Unknown
  10. The Bottom Line
  11. References

Why Kidneys and GLP-1 Receptors Are Connected

GLP-1 receptors aren't confined to the pancreas. They're expressed throughout the kidney — in podocytes, mesangial cells, proximal tubule cells, and endothelial cells of the glomerulus. In animal models, deleting the GLP-1 receptor gene produces albuminuria and glomerulosclerosis. Restoring GLP-1 signaling with liraglutide reversed those effects and reduced renal inflammation in both diabetic and non-diabetic kidney disease models.

This biology matters because it suggests GLP-1 agonists don't protect kidneys only by lowering blood sugar and body weight. Something more direct is happening at the tissue level — a hypothesis the clinical trial data now strongly supports.

The FLOW Trial: Semaglutide's Landmark Kidney Data

The FLOW trial (Evaluate Renal Function With Semaglutide Once Weekly) was a dedicated kidney outcomes trial — the first ever conducted with a GLP-1 receptor agonist. Published in the New England Journal of Medicine in May 2024, it answered a question the earlier cardiovascular outcome trials could only hint at: does semaglutide protect kidneys in people who already have established CKD?

Trial Design

ParameterDetail
Participants3,533 adults with type 2 diabetes and CKD
EligibilityeGFR 50-75 with UACR >300, or eGFR 25-50 with UACR >100
InterventionSemaglutide 1.0 mg weekly vs. placebo
Median follow-up3.4 years
Primary endpointComposite: kidney failure, ≥50% eGFR decline, kidney-related death, or CV death
Trial statusStopped early for efficacy

Primary Outcome

Semaglutide reduced the primary composite endpoint by 24% compared to placebo (HR 0.76; 95% CI 0.66-0.88; P = 0.0003). The event rates were 331 events in the semaglutide group versus 410 in the placebo group.

Key Secondary Results

OutcomeHazard Ratio95% CI
Kidney-specific composite0.790.66-0.94
Major adverse CV events (MACE)0.820.68-0.98
All-cause death0.800.67-0.95
CV death0.710.56-0.89
Annual eGFR slope difference+1.16 mL/min/1.73 m²/year—

The eGFR slope data deserve special attention. Over the course of the trial, semaglutide slowed the rate of kidney function decline by 1.16 mL/min/1.73 m² per year relative to placebo. In a disease where typical annual eGFR loss can be 3-5 mL/min in high-risk patients, this represents a meaningful preservation of kidney function over time. FLOW participants also experienced modest improvements in body weight, HbA1c, and blood pressure — consistent with metabolic benefits seen across semaglutide weight loss trials.

Subgroup Consistency

The treatment effect held across CKD severity categories — whether patients were stratified by baseline eGFR, UACR level, or KDIGO risk classification, the benefit remained consistent (P for interaction > 0.05 across all subgroups).

Heart Failure and CKD

A prespecified secondary analysis found semaglutide reduced the composite of heart failure events or CV death by 27%, heart failure events alone by 27%, and CV death by 29%. For patients with both CKD and type 2 diabetes — a population at extraordinarily high cardiovascular risk — these numbers are clinically significant.

Combination With SGLT2 Inhibitors

One of the most practical findings: semaglutide's benefits did not diminish when patients were already taking SGLT2 inhibitors. There was no heterogeneity of treatment effect based on SGLT2 inhibitor use. The safety profile of the combination was acceptable. This matters because SGLT2 inhibitors are already standard of care in diabetic CKD, and the data suggest the two drug classes work through complementary mechanisms.

Earlier Signals: LEADER, SUSTAIN-6, and REWIND

The FLOW trial didn't arrive out of nowhere. Three major cardiovascular outcome trials had already flagged kidney-protective effects — though none was designed to test that hypothesis directly.

LEADER (Liraglutide)

The LEADER trial enrolled 9,340 patients with type 2 diabetes and high cardiovascular risk, randomized to liraglutide 1.8 mg daily or placebo for a median of 3.8 years. The renal composite outcome (new macroalbuminuria, serum creatinine doubling, ESRD, or renal death) occurred less frequently with liraglutide, with an estimated relative risk reduction of about 22%. The effect was driven primarily by reductions in new-onset macroalbuminuria.

Liraglutide also produced measurable changes in risk markers: HbA1c dropped 1.4%, systolic blood pressure fell 3.0 mmHg, UACR decreased 13.2%, and body weight declined 2.3 kg — all compared to placebo (NEJM, 2017).

SUSTAIN-6 (Semaglutide)

SUSTAIN-6 tested subcutaneous semaglutide (0.5 mg and 1.0 mg weekly) in 3,297 patients with type 2 diabetes and high cardiovascular risk over 104 weeks. The risk of new or worsening nephropathy was 36% lower with semaglutide versus placebo.

The albuminuria data were striking. At week 104, UACR was reduced by 25% with semaglutide 0.5 mg and 34% with semaglutide 1.0 mg, relative to placebo. In patients with pre-existing micro- or macroalbuminuria, the reductions were even more pronounced.

The eGFR pattern followed what's now recognized as typical for GLP-1 agonists: an initial acute dip in the first 16 weeks (about 1.3-1.6 mL/min/1.73 m²), followed by stabilization. By week 104, the overall eGFR trajectory was no different from placebo — but the albuminuria reductions were persistent.

REWIND (Dulaglutide)

REWIND tested dulaglutide 1.5 mg weekly in 9,901 patients over a median of 5.4 years — the longest follow-up of any GLP-1 cardiovascular outcome trial. The renal composite (macroalbuminuria, sustained 30% eGFR decline, or renal replacement therapy) was reduced by 15% (HR 0.85; 95% CI 0.77-0.93; P = 0.0004).

A later post hoc analysis focused on harder kidney endpoints — excluding macroalbuminuria and looking at sustained ≥40% eGFR decline, ESRD, or renal death. Even with this stricter definition, dulaglutide reduced the composite by 25% (HR 0.75; 95% CI 0.62-0.92; P = 0.004). The annual eGFR decline was 0.19 mL/min/1.73 m² per year slower with dulaglutide versus placebo (Diabetes Care, 2023).

Pooled Analysis: SUSTAIN-6 + LEADER

A pooled analysis combining SUSTAIN-6 and LEADER data found that semaglutide and liraglutide together lowered albuminuria by 24% versus placebo at two years. The annual eGFR slope difference was 0.59 mL/min/1.73 m² favoring GLP-1 treatment. The benefit was largest in patients with baseline eGFR between 30 and 60 mL/min/1.73 m² — precisely the group at highest risk of progression (Circulation, 2022).

SELECT Trial: Kidney Protection Without Diabetes

One of the more intriguing findings came from the SELECT trial, which tested semaglutide 2.4 mg weekly in 17,604 patients with overweight or obesity and established cardiovascular disease — but without diabetes.

A secondary analysis published in Nature Medicine in 2024 showed semaglutide reduced the five-component kidney composite endpoint by 22% (HR 0.78; 95% CI 0.63-0.96; P = 0.02). The incidence was 1.8% with semaglutide versus 2.2% with placebo.

This is significant because it suggests the kidney benefits of GLP-1 agonists aren't simply a downstream effect of better glucose control. Something about these drugs protects kidneys independent of diabetes management — a finding that aligns with the preclinical evidence showing direct GLP-1 receptor-mediated effects on renal tissue.

A separate randomized trial published in Nature Medicine in early 2025 specifically tested semaglutide in people with CKD, overweight or obesity, and no diabetes. While full results are still being evaluated, this trial extends the evidence base beyond the diabetic CKD population.

Tirzepatide and Kidney Outcomes

Tirzepatide — the dual GIP/GLP-1 receptor agonist — doesn't yet have a dedicated kidney outcomes trial. But the available data are encouraging.

SURPASS-4

In SURPASS-4, which compared tirzepatide (5, 10, or 15 mg weekly) with insulin glargine in 1,995 patients with type 2 diabetes and high cardiovascular risk, a post hoc analysis found tirzepatide nearly halved the risk of a pre-specified kidney composite endpoint (eGFR decline ≥40%, renal death, kidney failure, or new-onset macroalbuminuria). The rate of new macroalbuminuria was notably lower with tirzepatide (HR 0.41).

SURPASS-CVOT: Tirzepatide vs. Dulaglutide

The SURPASS-CVOT trial compared tirzepatide to dulaglutide (itself a proven kidney-protective GLP-1 agonist) in 13,165 patients with type 2 diabetes. Among the 1,241 patients with very high-risk CKD, tirzepatide reduced the composite kidney outcome by 33% compared to dulaglutide (HR 0.67; 95% CI 0.52-0.87; P = 0.002). The event rates were 16.7% with tirzepatide versus 23.0% with dulaglutide.

Pooled Albuminuria Analysis (SURPASS 1-5)

A pooled analysis across the SURPASS 1-5 trials confirmed that tirzepatide reduces albuminuria regardless of whether patients are also taking RAS inhibitors or SGLT2 inhibitors — suggesting the effect is additive to existing kidney-protective therapies.

These results are promising, but a dedicated kidney outcomes trial for tirzepatide would be needed to confirm the drug's place alongside semaglutide in CKD management.

How GLP-1 Agonists Protect the Kidneys

The kidney benefits of GLP-1 agonists appear to work through at least four distinct pathways:

1. Natriuresis and hemodynamic effects. GLP-1 agonists inhibit the sodium-hydrogen exchanger 3 (NHE3) in proximal tubule cells, promoting sodium and water excretion. This reduces intraglomerular pressure and counteracts the hyperfiltration that drives CKD progression. Liraglutide also stimulates atrial natriuretic peptide (ANP) release from cardiomyocytes, amplifying the natriuretic effect.

2. Anti-inflammatory signaling. GLP-1 agonists suppress NF-kB activation and reduce production of TNF-alpha, IL-1-beta, and other proinflammatory cytokines in renal tissue. In animal models, these effects occur at the level of podocytes and mesangial cells — independent of changes in blood glucose.

3. Oxidative stress reduction. Exendin-4 (the parent compound of exenatide) reduced albuminuria, glomerular hypertrophy, and mesangial matrix expansion in diabetic rats without lowering blood glucose, primarily by inhibiting reactive oxygen species generation.

4. RAAS modulation. GLP-1 agonists reduce angiotensin II levels and downstream signaling in the glomerulus, providing an additional mechanism of renoprotection that may complement ACE inhibitors and ARBs.

An important detail: a mediation analysis of the LEADER and SUSTAIN-6 trials found that HbA1c changes explained only 25-26% of the kidney-protective effect, and systolic blood pressure reductions explained 9-22%. That leaves more than half of the benefit unexplained by conventional risk factors — pointing to these direct renal mechanisms as the primary drivers.

The ongoing REMODEL study (NCT04865770) is using kidney MRI and biopsies to directly measure changes in inflammation, fibrosis, perfusion, and oxygenation with semaglutide treatment. Results from this study should provide the most detailed mechanistic picture yet.

Meta-Analysis Data Across the GLP-1 Class

Two large meta-analyses published in late 2024 quantify the class-wide kidney effects of GLP-1 agonists.

A Lancet Diabetes & Endocrinology meta-analysis pooled 11 trials involving 85,373 participants:

Outcome (Type 2 Diabetes Population)Hazard Ratio95% CI
Composite kidney outcome0.820.73-0.93
Kidney failure0.840.72-0.99
MACE0.870.81-0.93
All-cause death0.880.83-0.93

A second meta-analysis covering 19 randomized controlled trials found GLP-1 agonists reduced the primary renal outcome by 19% (RR 0.81; 95% CI 0.73-0.89), microalbuminuria by 24% (RR 0.76; 95% CI 0.71-0.82), and slowed yearly eGFR loss by 0.45 mL/min/1.73 m².

In patients with baseline eGFR < 60 mL/min/1.73 m² specifically — a population with established CKD — GLP-1 agonists were associated with a 15% reduction in the composite kidney outcome (OR 0.85; 95% CI 0.77-0.94). The magnitude of eGFR decline reduction increased with CKD severity: a 22% reduction in ≥30% eGFR decline, 24% for ≥40% decline, and 28% for ≥50% decline.

Importantly, there were no excess rates of serious adverse events, acute pancreatitis, or severe hypoglycemia in the GLP-1 agonist groups compared to placebo.

FDA Approval and Clinical Practice

On January 28, 2025, the FDA approved Ozempic (semaglutide) for a new indication: reducing the risk of worsening kidney disease, kidney failure, and cardiovascular death in adults with type 2 diabetes and CKD. This made semaglutide the first and only GLP-1 receptor agonist with an FDA-approved kidney disease indication.

The approval — based on the FLOW trial data — applies to all three Ozempic doses (0.5 mg, 1 mg, and 2 mg) and adds to its existing indications for glycemic control and cardiovascular risk reduction. The European Medicines Agency's CHMP adopted a positive opinion for the same label expansion in December 2024.

The "Four Pillars" of CKD Treatment

Nephrologists now describe four pillars of therapy for patients with CKD and type 2 diabetes:

  1. RAS blockade — ACE inhibitors or ARBs
  2. SGLT2 inhibitors — dapagliflozin or empagliflozin
  3. Finerenone — non-steroidal mineralocorticoid receptor antagonist
  4. Semaglutide — GLP-1 receptor agonist (the newest addition)

Each class works through different mechanisms, and the FLOW trial's subgroup data showing benefit regardless of SGLT2 inhibitor or MRA co-use supports a multi-drug approach. For a broader perspective on how peptides intersect with diabetes management, the overlapping mechanisms of these drug classes make combination therapy increasingly practical.

What's Still Unknown

Despite the strong evidence, several questions remain open:

Non-diabetic CKD. The FLOW trial enrolled only patients with type 2 diabetes. Early data from the SELECT trial and a 2025 trial in CKD patients without diabetes are promising, but we don't yet have large-scale confirmation that GLP-1 agonists protect kidneys in the absence of diabetes.

Tirzepatide's kidney profile. The SURPASS data are encouraging, and the SURPASS-CVOT comparison against dulaglutide was striking. But tirzepatide still lacks a dedicated kidney outcomes trial. Whether dual GIP/GLP-1 agonism offers advantages over GLP-1 agonism alone for kidney protection is unknown.

Optimal combination sequencing. Clinicians now have four drug classes to layer on top of each other. The best order of introduction, the interactions between them, and whether there's a ceiling to benefit from adding a fourth agent — these are all unanswered.

Mechanisms beyond inflammation. The REMODEL study and future biopsy-based research should clarify whether GLP-1 agonists reduce kidney fibrosis, improve tubular oxygenation, or alter specific cell populations. Current evidence is heavily based on animal models.

Long-term outcomes. The FLOW trial's median follow-up was 3.4 years. CKD progresses over decades. Whether the benefits persist, amplify, or plateau over longer timeframes is a question only extended follow-up studies can answer.

The Bottom Line

The evidence for GLP-1 receptor agonists in kidney disease has moved from intriguing secondary signals to hard outcome data. The FLOW trial proved that semaglutide reduces kidney failure, slows eGFR decline, and cuts cardiovascular death in people with type 2 diabetes and CKD — benefits that held regardless of baseline kidney function, albuminuria level, or use of other kidney-protective drugs.

Class-wide meta-analyses confirm these aren't semaglutide-specific effects. Liraglutide, dulaglutide, and tirzepatide all show kidney-protective signals, though semaglutide currently has the strongest dedicated evidence and the only FDA-approved kidney indication.

For patients with type 2 diabetes and CKD, semaglutide now belongs alongside RAS inhibitors, SGLT2 inhibitors, and finerenone as a standard treatment option. For patients without diabetes, the evidence is emerging but not yet definitive.

As with all peptide-based therapies, treatment decisions should be made with a physician who can weigh individual risk factors, existing medications, and evolving guidelines. The science is moving quickly — the 2024-2025 period has reshaped how nephrologists think about GLP-1 agonists, and dedicated CKD trials for tirzepatide and oral semaglutide are likely to follow.

References

  1. 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

  2. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-848. NEJM

  3. Mann JFE, Buse JB, Idorn T, et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation. 2022;145(8):575-585. AHA Journals

  4. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and kidney function-related outcomes in type 2 diabetes: a REWIND post hoc analysis. Diabetes Care. 2023;46(8):1524-1530. Diabetes Care

  5. Colhoun HM, Lingvay I, Brown PM, et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat Med. 2024. Nature Medicine

  6. Heerspink HJL, Sattar N, Pavo I, et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial. Clin Kidney J. 2023;16(5):797-803. PMC

  7. Rossing P, Baeres FMM, Bakris G, et al. The rationale, design, and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant. 2023.

  8. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2024. Lancet

  9. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394(10193):131-138. Lancet

  10. FDA approves Ozempic (semaglutide) as the only GLP-1 RA to reduce the risk of worsening kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease. Novo Nordisk press release. January 28, 2025. JAMA

  11. Rossing P, Bækdal M, Bang-Christensen K, et al. Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial. Nat Med. 2025. PubMed

  12. Tirzepatide associated with reduced albuminuria in participants with type 2 diabetes: pooled post hoc analysis from the randomized active- and placebo-controlled SURPASS-1-5 clinical trials. Diabetes Care. 2025;48(3):430. Diabetes Care

Last reviewed: February 2025. PeptideJournal.org provides educational content only and does not sell peptides or provide medical advice. Consult a healthcare provider before making treatment decisions.