Kidney evidence arrived here the long way around. Nobody set out to test these drugs on kidneys; the signal kept appearing as a secondary endpoint in trials built to count heart attacks, and it kept pointing the same direction. FLOW was the trial that finally asked the question on purpose, in people who already had chronic kidney disease, and it was halted early because the answer was clear enough that continuing would have been hard to justify. The nine papers around it trace how the suspicion accumulated — from liraglutide slowing nephropathy in 2017, through a dedicated trial in advanced disease, to the analysis showing the benefit survives on top of an SGLT2 inhibitor.
Ranked papers
#1FLOW
Perkovic V, Tuttle KR, Rossing P, et al. · N Engl J Med · 2024
What it measured: Kidney failure, losing half of kidney function, or dying of kidney or heart disease
The only kidney trial in the class that was designed as one. 3,533 patients whose type 2 diabetes had already produced established kidney disease, given semaglutide 1.0 mg against placebo and halted at a median 3.4 years, because the benefit was unambiguous. The kidney endpoint fell 24%, major cardiovascular events 18%, and death from any cause 20%. It produced the January 2025 kidney indication for Ozempic, the first label in this class granted for something other than glucose or weight.
PMID 38785209 ↗NCT03819153 ↗DOI 10.1056/NEJMoa2403347 ↗
#2LEADER (renal)
Mann JFE, Ørsted DD, Brown-Frandsen K, et al. · N Engl J Med · 2017
What it measured: Protein appearing in urine, kidney function halving, kidney failure, or kidney death
The pre-specified renal analysis of LEADER, and the first randomized evidence that any drug in this class slows diabetic kidney disease. Across 9,340 patients over a median 3.84 years, the renal composite came in at 5.7% against 7.2% — a 22% reduction. ⚠ Read the driver carefully: almost all of it was less new macroalbuminuria, which is protein appearing in urine rather than kidneys actually failing. A real finding, and a softer endpoint than the name suggests.
PMID 28854085 ↗NCT01179048 ↗DOI 10.1056/NEJMoa1616011 ↗
#3AWARD-7
Tuttle KR, Lakshmanan MC, Rayner B, et al. · Lancet Diabetes Endocrinol · 2018
What it measured: Blood sugar at 26 weeks, with the rate of kidney decline as the key secondary
The first trial to take a GLP-1 into moderate-to-severe kidney disease, where most diabetes drugs are restricted or contraindicated. 577 adults at stage 3 or 4 were given dulaglutide or insulin titrated to target. Blood sugar control matched, but kidney function declined far less on the drug — 0.7 against 3.3 mL/min over 52 weeks. Its value is as much practical as scientific: it established that these drugs can be used at all in patients who have run out of options.
PMID 29910024 ↗NCT01621178 ↗DOI 10.1016/S2213-8587(18)30104-9 ↗
#4REWIND (renal)
Gerstein HC, Colhoun HM, Dagenais GR, et al. · Lancet · 2019
What it measured: Protein appearing in urine, a sustained 30% loss of kidney function, or needing dialysis
REWIND's renal analysis, over a median 5.4 years — the longest follow-up available. The composite fell from 19.6% to 17.1%, a 15% reduction, with new macroalbuminuria down 23%. What makes it distinctive is the population: 69% had never had a cardiovascular event, so this is the strongest kidney evidence in the class for people who are not already sick. ⚠ It was an exploratory analysis, which is a weaker footing than a pre-specified one.
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
What it measured: First major cardiac event, with a kidney measure as secondary
4,076 patients with cardiovascular or kidney disease, where the pre-specified renal composite fell 32%. ★ The detail worth extracting: 15% were already on an SGLT2 inhibitor, and the kidney benefit held anyway. That was the first randomized indication that the two drug classes do not merely overlap — they add. The drug itself was discontinued before reaching market, so the finding outlived the product.
PMID 34215025 ↗NCT03496298 ↗DOI 10.1056/NEJMoa2108269 ↗
#6SURPASS-4 (kidney)
Heerspink HJL, Sattar N, Pavo I, et al. · Lancet Diabetes Endocrinol · 2022
What it measured: Losing 40% of kidney function, kidney failure or death, or new protein in urine
The kidney analysis from SURPASS-4, and the only such evidence for a dual GIP/GLP-1 agonist. 1,995 high-risk patients on tirzepatide against titrated insulin over a median 85 weeks, with the kidney composite at 4.0% against 6.3% — a 41% reduction — and kidney function declining at 1.4 rather than 3.6 mL/min a year. ⚠ The comparator is insulin, not placebo, which makes this a statement about relative benefit rather than absolute.
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
What it measured: First major cardiac event, with kidney disease planned as a secondary measure
The nephropathy composite inside SUSTAIN-6, eight years before anyone ran FLOW. Across 3,297 patients over 104 weeks it came in at 3.8% against 6.1% — a 36% reduction. This was the earliest randomized hint that semaglutide specifically does something for kidneys, and in retrospect it is the observation that made the dedicated trial worth funding.
PMID 27633186 ↗NCT01720446 ↗DOI 10.1056/NEJMoa1607141 ↗
#8ELIXA (renal)
Muskiet MHA, Tonneijck L, Huang Y, et al. · Lancet Diabetes Endocrinol · 2018
What it measured: Protein leaking into the urine, measured at just over two years
The renal analysis of the trial that found nothing for the heart. Among patients who already had macroalbuminuria, lixisenatide reduced urinary protein 39% more than placebo — but kidney function decline did not differ. ★ Its importance is as a floor: even a short-acting GLP-1 with no cardiovascular benefit whatsoever still moved albuminuria. That tells you albuminuria is the easiest endpoint in this field to move, and should temper how much weight it carries elsewhere.
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
What it measured: The same kidney measure, split by whether patients were already on an SGLT2 inhibitor
The subgroup analysis that answers the question every nephrologist asks: does this still work if the patient is already on an SGLT2 inhibitor? Of FLOW's 3,533 participants, 550 were. The hazard ratios came out at 0.73 without and 0.75 with — statistically indistinguishable. The benefits are additive, and the guidelines recommending both together rest substantially on this analysis.
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
What it measured: Cardiac and kidney outcomes pooled across eight cardiovascular trials
The class-level meta-analysis that set the pre-FLOW baseline, pooling eight cardiovascular trials and 60,080 patients. The kidney composite fell 21%. ⚠ And here is the honest caveat the headline hides: the albuminuria component drove almost all of it, with much weaker signals for actual loss of kidney function or progression to dialysis. Useful as a benchmark, and not the same claim as preventing kidney failure.
PMID 34425083 ↗DOI 10.1016/S2213-8587(21)00203-5 ↗
About this list
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 2026-08-16. Each paper card links directly to PubMed and to ClinicalTrials.gov where applicable.
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