Until 2024, the kidney evidence for GLP-1 receptor agonists came almost entirely from secondary or post-hoc renal-composite endpoints embedded in cardiovascular outcomes trials. FLOW changed that — it was the first dedicated phase-3 kidney-outcomes trial of a GLP-1 (semaglutide 1.0 mg) in patients with type 2 diabetes and chronic kidney disease, was stopped early for efficacy, and drove the January 2025 FDA kidney indication for Ozempic. The other nine papers below trace the longer evidence arc: the 2017 LEADER renal-outcomes paper that first showed liraglutide slows nephropathy progression; the 2018 AWARD-7 head-to-head against insulin in moderate-to-severe CKD; renal-composite secondary analyses from SUSTAIN-6, REWIND, AMPLITUDE-O, ELIXA, and SURPASS-4; the FLOW SGLT2-interaction analysis confirming additive benefit; and the Sattar/Kristensen 2021 class-level meta-analysis quantifying the 21% relative kidney-composite reduction across the class.
Ranked papers
#1FLOW
Perkovic V, Tuttle KR, Rossing P, et al. · N Engl J Med · 2024
Primary endpoint: Composite kidney failure, ≥50% eGFR decline, kidney or cardiovascular death
FLOW is the only dedicated kidney-outcomes randomized trial of a GLP-1 receptor agonist. It enrolled 3,533 patients with type 2 diabetes and chronic kidney disease (eGFR 25-75, UACR 100-5,000) and randomized them to semaglutide 1.0 mg weekly or placebo. The trial was stopped early for efficacy after a median 3.4 years. The composite primary kidney endpoint occurred 24% less often on semaglutide (HR 0.76, 95% CI 0.66-0.88, p=0.0003). Three-point MACE fell 18% and all-cause mortality 20%. FLOW drove the January 2025 FDA kidney indication for Ozempic — the first non-glycemic kidney label for the class.
PMID 38785209 ↗NCT03819153 ↗DOI 10.1056/NEJMoa2403347 ↗
#2LEADER (renal)
Mann JFE, Ørsted DD, Brown-Frandsen K, et al. · N Engl J Med · 2017
Primary endpoint: Composite new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, ESRD, or renal death
This pre-specified secondary analysis of the LEADER cardiovascular outcomes trial (9,340 high-risk type 2 diabetes patients) reported renal outcomes after a median 3.84 years on liraglutide 1.8 mg vs placebo. The composite renal endpoint occurred in 5.7% on liraglutide vs 7.2% on placebo — a 22% relative risk reduction (HR 0.78, 95% CI 0.67-0.92, p=0.003). The effect was driven almost entirely by reduced new-onset persistent macroalbuminuria. This was the first published evidence that a GLP-1 receptor agonist slows the progression of diabetic kidney disease.
PMID 28854085 ↗NCT01179048 ↗DOI 10.1056/NEJMoa1616011 ↗
#3AWARD-7
Tuttle KR, Lakshmanan MC, Rayner B, et al. · Lancet Diabetes Endocrinol · 2018
Primary endpoint: HbA1c change at week 26 (eGFR slope as key secondary)
AWARD-7 was the first dedicated GLP-1 trial in patients with moderate-to-severe CKD. 577 adults with type 2 diabetes and stage 3-4 CKD (eGFR 15-60) were randomized to dulaglutide 1.5 mg weekly, dulaglutide 0.75 mg, or insulin glargine titrated to target. Glycemic control was non-inferior across arms, but eGFR declined less on dulaglutide 1.5 mg (-0.7 vs -3.3 mL/min/1.73 m² with glargine at 52 weeks). Macroalbuminuria progression was also reduced. Established that GLP-1 therapy is safe and effective in advanced CKD where many other antidiabetic options are restricted.
PMID 29910024 ↗NCT01621178 ↗DOI 10.1016/S2213-8587(18)30104-9 ↗
#4REWIND (renal)
Gerstein HC, Colhoun HM, Dagenais GR, et al. · Lancet · 2019
Primary endpoint: Composite new macroalbuminuria, sustained 30% eGFR decline, or chronic renal replacement therapy
This exploratory renal analysis of REWIND followed 9,901 type 2 diabetes patients on dulaglutide 1.5 mg weekly vs placebo over a median 5.4 years — the longest GLP-1 CVOT to date. The composite renal endpoint occurred in 17.1% on dulaglutide vs 19.6% on placebo — a 15% relative risk reduction (HR 0.85, 95% CI 0.77-0.93, p=0.0004). New macroalbuminuria fell 23%. Because 69% of REWIND participants had no prior cardiovascular event, this analysis provided the strongest primary-prevention kidney signal in the class.
PMID 31189509 ↗NCT01394952 ↗DOI 10.1016/S0140-6736(19)31150-X ↗
#5AMPLITUDE-O
Gerstein HC, Sattar N, Rosenstock J, et al. · N Engl J Med · 2021
Primary endpoint: First MACE; renal composite (decrease in eGFR ≥40%, ESRD, or death due to renal causes) as secondary
AMPLITUDE-O randomized 4,076 type 2 diabetes patients with established cardiovascular disease or kidney disease plus risk factors to efpeglenatide 4 or 6 mg weekly or placebo over a median 1.8 years. The pre-specified composite renal endpoint (≥40% eGFR decline, ESRD, or renal death) occurred 32% less often on efpeglenatide (HR 0.68, 95% CI 0.57-0.79, p<0.001). Notably, 15% of participants were already taking an SGLT2 inhibitor and the kidney benefit was preserved — the first randomized evidence that GLP-1 + SGLT2 effects are additive on the kidney.
PMID 34215025 ↗NCT03496298 ↗DOI 10.1056/NEJMoa2108269 ↗
#6SURPASS-4 (kidney)
Heerspink HJL, Sattar N, Pavo I, et al. · Lancet Diabetes Endocrinol · 2022
Primary endpoint: Composite eGFR decline ≥40%, kidney failure, renal death, or new-onset macroalbuminuria; eGFR slope
This pre-specified kidney analysis of SURPASS-4 followed 1,995 type 2 diabetes patients at high cardiovascular risk on tirzepatide (5, 10, or 15 mg pooled) vs titrated insulin glargine over a median 85 weeks. The composite kidney endpoint occurred in 4.0% on tirzepatide vs 6.3% on glargine — a 41% relative risk reduction (HR 0.58, 95% CI 0.43-0.80). Annualized eGFR decline was −1.4 (tirzepatide) vs −3.6 mL/min/1.73 m²/year (glargine). The first kidney-outcome evidence for a dual GIP/GLP-1 agonist — supporting an ongoing phase-3 dedicated CKD program.
PMID 36152639 ↗NCT03730662 ↗DOI 10.1016/S2213-8587(22)00243-1 ↗
#7SUSTAIN-6 (nephropathy composite)
Marso SP, Bain SC, Consoli A, et al. · N Engl J Med · 2016
Primary endpoint: First MACE; new or worsening nephropathy as pre-specified secondary
SUSTAIN-6 was a pre-approval cardiovascular safety trial for injectable semaglutide in 3,297 type 2 diabetes patients at high cardiovascular risk over 104 weeks. The pre-specified secondary 'new or worsening nephropathy' composite (persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement, or renal death) occurred in 3.8% on semaglutide vs 6.1% on placebo — a 36% relative risk reduction (HR 0.64, 95% CI 0.46-0.88, p=0.005). This was the earliest randomized signal that semaglutide slowed nephropathy progression, foreshadowing FLOW eight years later.
PMID 27633186 ↗NCT01720446 ↗DOI 10.1056/NEJMoa1607141 ↗
#8ELIXA (renal)
Muskiet MHA, Tonneijck L, Huang Y, et al. · Lancet Diabetes Endocrinol · 2018
Primary endpoint: Change in urine albumin-to-creatinine ratio (UACR) at 108 weeks
This exploratory renal analysis of ELIXA followed 6,068 type 2 diabetes patients with recent acute coronary syndrome on lixisenatide vs placebo over a median 108 weeks. Among participants with macroalbuminuria at baseline, lixisenatide reduced UACR by 39% more than placebo (-1.69 vs +0.28 log mg/g, p=0.0070). Composite new macroalbuminuria or doubling of UACR was reduced. eGFR decline did not differ. Because ELIXA was the first GLP-1 CVOT and was neutral on MACE, this renal signal is important as the lower bound — even a short-acting GLP-1 with no MACE benefit improved albuminuria.
PMID 30292589 ↗NCT01147250 ↗DOI 10.1016/S2213-8587(18)30268-7 ↗
#9FLOW (SGLT2 interaction)
Mann JFE, Rossing P, Bakris G, et al. · Nat Med · 2024
Primary endpoint: Composite kidney failure, ≥50% eGFR decline, kidney or cardiovascular death, stratified by baseline SGLT2 inhibitor use
This pre-specified FLOW subgroup analysis tested whether semaglutide's kidney benefit holds in patients already taking an SGLT2 inhibitor. Of 3,533 participants, 550 (15.6%) were on an SGLT2i at baseline. The composite primary kidney endpoint hazard ratios were 0.73 (no SGLT2i at baseline) and 0.75 (SGLT2i at baseline) — effectively identical (p-interaction = 0.91). All-cause mortality, MACE, and eGFR-slope effects were also consistent. Established that GLP-1 + SGLT2 inhibitor effects on the kidney are additive and supported guideline recommendations for combination therapy in CKD.
PMID 38914124 ↗NCT03819153 ↗DOI 10.1038/s41591-024-03133-0 ↗
#10GLP-1 class meta-analysis
Sattar N, Lee MMY, Kristensen SL, et al. · Lancet Diabetes Endocrinol · 2021
Primary endpoint: Three-point MACE and composite kidney outcome pooled across eight CVOTs
This pre-FLOW class-level meta-analysis pooled eight GLP-1 cardiovascular outcomes trials covering 60,080 type 2 diabetes patients (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY OUTCOMES, REWIND, PIONEER 6, AMPLITUDE-O). The composite kidney outcome (macroalbuminuria, doubling serum creatinine or ≥40% eGFR decline, ESRD, or renal death) was reduced 21% (HR 0.79, 95% CI 0.73-0.87, p<0.0001). The albuminuria component drove the effect, with smaller signals for eGFR loss and ESRD. Sets the pre-FLOW class baseline against which the dedicated CKD trial expanded the indication.
PMID 34425083 ↗DOI 10.1016/S2213-8587(21)00203-5 ↗
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We curate ranked, citation-anchored PubMed paper lists for the most-searched questions in obesity medicine. Every citation on this page was checked against PubMed on August 2026. Each paper card links directly to PubMed and to ClinicalTrials.gov where applicable.
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