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GLP-1 receptor agonists and emerging therapy

TL;DR — FLOW provided a dedicated kidney-outcome trial for semaglutide in type 2 diabetes and CKD, reducing the primary composite by 24% relative to placebo (HR 0.76, 95% CI 0.66–0.88) (Perkovic 2024, PMID 38785209). A prespecified analysis did not show evidence that concomitant baseline SGLT2-inhibitor use modified the effect, but the subgroup was small and not randomized to combination (Mann 2024, PMID 38914124). A prespecified pooled analysis of SELECT, FLOW and SOUL (30,787 participants, mean follow-up 39.5–47.5 months) extended the kidney signal beyond FLOW's diabetic-CKD population, reducing a kidney composite by 16% (973 vs 1,134 first events; HR 0.84, 95% CI 0.77–0.91) and a narrower kidney composite excluding cardiovascular death by 20% (HR 0.80, 0.69–0.92) across oral and injectable semaglutide (Mann 2026, PMID 42567173). Modelling suggests large lifetime gains from four-class therapy; as of 2026-09-02 no factorial outcomes trial has established sequence or full combination benefit, though CONFIDENCE has randomized the finerenone–empagliflozin pair on albuminuria (Neuen 2024, PMID 37952217) (Agarwal 2025, PMID 40470996). Bardoxolone remains a cautionary case: a drug that improved eGFR but increased heart-failure events and led to early trial termination (de Zeeuw 2013, PMID 24206459).

FLOW

FLOW enrolled people with type 2 diabetes and CKD and measured a kidney-major composite, moving GLP-1 evidence beyond albuminuria-only inference (Perkovic 2024, PMID 38785209).

Concomitant SGLT2 inhibition

The comparison by baseline SGLT2 use was observational within randomized FLOW assignment; absence of interaction is not proof of additive combination efficacy (Mann 2024, PMID 38914124).

Four-pillar modelling

Neuen's estimates are actuarial projections applying pooled relative effects from 2 SGLT2-inhibitor, 2 non-steroidal MRA and 8 GLP-1 trials to CANVAS and CREDENCE control participants: combination versus conventional care gave a modelled MACE hazard ratio of 0.65 (95% CI 0.55–0.76), a 3-year absolute risk reduction of 4.4% (3.0–5.7), and for a 50-year-old a projected 3.2 additional MACE-free years and 5.5 additional years free of CKD progression. These are model outputs assuming transportability and independence, not observed randomized follow-up, and remain hypothesis-generating for sequencing trials (Neuen 2024, PMID 37952217). The first randomized combination read-out, CONFIDENCE, tested only two of the four classes and only on 180-day albuminuria (Agarwal 2025, PMID 40470996).

Surrogates and failure

In BEACON, 2,185 patients with type 2 diabetes and stage 4 CKD received bardoxolone methyl or placebo. eGFR, blood pressure and uACR all rose significantly with the drug, yet the primary composite of ESRD or cardiovascular death was unchanged (6% versus 6%; HR 0.98, 95% CI 0.70–1.37) and heart-failure hospitalization or death rose sharply (96 versus 55 patients; HR 1.83, 95% CI 1.32–2.55, P<0.001), prompting termination at median 9 months (de Zeeuw 2013, PMID 24206459). It illustrates why filtration changes mislead when haemodynamics and fluid balance shift.

Emerging endpoints

Future trials need hard kidney outcomes, chronic slope, symptoms, treatment burden and safety, not albuminuria alone.

Scope border

Weight and glycaemic endpoints are linked to the diabetes conditions; this page reports kidney outcomes and CKD-specific uncertainty.

FLOW and the emerging-therapy guardrail

Quantity FLOW result Boundary
Participants 3,533 Type 2 diabetes plus albuminuric CKD
Median follow-up 3.4 years Trial stopped early after interim review
Primary major kidney event 331 vs 410; HR 0.76 (0.66–0.88) Composite includes kidney/CV death (Perkovic 2024, PMID 38785209)
Kidney-specific composite HR 0.79 (0.66–0.94) Prespecified secondary analysis
eGFR-slope difference +1.16 mL/min/1.73 m²/year Surrogate plus clinical outcomes
Major cardiovascular events HR 0.82 (0.68–0.98) Hierarchical confirmatory endpoint
All-cause death HR 0.80 (0.67–0.95) Same population
Baseline SGLT2 subgroup No detected heterogeneity Concomitant use was not randomized (Mann 2024, PMID 38914124)
Bardoxolone precedent eGFR rose; HF hospitalization/death HR 1.83 (1.32–2.55); primary composite HR 0.98 (0.70–1.37) Intermediate filtration change can mislead (de Zeeuw 2013, PMID 24206459)
Semaglutide beyond FLOW Pooled SELECT+FLOW+SOUL kidney composite HR 0.84 (0.77–0.91); n=30,787 Includes participants without diabetes; pooled across doses and routes (Mann 2026, PMID 42567173)

Kidney benefit outside diabetes: SELECT

FLOW established the kidney effect of semaglutide in type 2 diabetes with CKD. SELECT tested the same drug in 17,604 people with overweight or obesity and established cardiovascular disease but without diabetes. The prespecified composite kidney endpoint — death from kidney disease, initiation of chronic kidney replacement therapy, persistent eGFR below 15, persistent ≥50% eGFR reduction, or onset of persistent macroalbuminuria — occurred in 1.8% on semaglutide 2.4 mg weekly versus 2.2% on placebo (HR 0.78, 95% CI 0.63–0.96; p = 0.02). The eGFR treatment benefit at 104 weeks was 0.75 mL/min/1.73 m² (95% CI 0.43–1.06; p < 0.001) overall and 2.19 (1.00–3.38; p < 0.001) in those with baseline eGFR below 60 (Colhoun 2024, PMID 38796653). Event rates are low because SELECT was not a CKD trial, so the confidence interval is wide and the absolute benefit small — but the direction extends the kidney signal beyond diabetes, which FLOW alone could not do.

Does GLP-1 benefit persist on top of SGLT2 inhibition?

The practically decisive question for a stacked regimen is whether the two classes are additive. Pooling the three GLP-1 receptor agonist outcome trials that reported effects by baseline SGLT2 inhibitor use — 1,743 of 17,072 participants (10.2%) on an SGLT2 inhibitor at randomisation — GLP-1 receptor agonists reduced major adverse cardiovascular events by 21% overall (HR 0.79, 95% CI 0.71–0.87), with consistent effects in those receiving and not receiving SGLT2 inhibitors (HR 0.77, 0.54–1.09 versus 0.79, 0.71–0.87; p-heterogeneity 0.78). Heart-failure hospitalisation showed the same consistency (HR 0.58, 0.36–0.93 versus 0.73, 0.63–0.85; p-heterogeneity 0.26), and the composite kidney outcome was reduced overall (RR 0.79, 0.66–0.95) (Neuen 2024, PMID 39210781).

The caveat is sample size, not direction: 1,743 participants on background SGLT2 inhibition cannot exclude a modest interaction, and the FLOW subgroup analysis (PMID 38914124) is subject to the same limit. A Cochrane review covering GLP-1 receptor agonists across all CKD stages in diabetes summarises the wider evidence base and its gaps, including the near-absence of data in CKD stages 4–5 and on dialysis (Natale 2025, PMID 39963952).

Endothelin antagonism: the closest thing to a fourth pillar

Combined with SGLT2 inhibition. ZENITH-CKD randomized 447 treated participants (mean age 62.8 ± 12.1, mean eGFR 46.7 ± 22.4 mL/min/1.73 m², median uACR 565.5 mg/g, IQR 243.0–1,212.6) at 170 sites in 18 countries to zibotentan 1.5 mg plus dapagliflozin, zibotentan 0.25 mg plus dapagliflozin, or dapagliflozin plus placebo for 12 weeks on background RAS blockade. Both zibotentan doses reduced uACR versus dapagliflozin alone, with fluid retention — defined prospectively as ≥3% weight gain (≥2.5% from total body water) or a ≥100% BNP rise above defined thresholds — as the event of special interest (Heerspink 2023, PMID 37931629). Fluid retention is the historical reason endothelin antagonists failed in CKD, and pairing one with an SGLT2 inhibitor is an explicit attempt to engineer around it (Smeijer 2024, PMID 39352861).

As a disease-specific therapy. ALIGN randomized 404 adults with biopsy-proven IgA nephropathy, eGFR ≥30 and proteinuria ≥1.0 g/day on RAS blockade, across 133 sites in 20 countries, to atrasentan 0.75 mg daily or placebo for 132 weeks. In the main stratum (n = 340), eGFR change from baseline to week 136 was −7.5 mL/min/1.73 m² (95% CI −9.2 to −5.8) with atrasentan and −9.9 (−11.7 to −8.1) with placebo — a between-group difference of 2.4 (95% CI −0.1 to 4.8; p = 0.057), narrowly missing significance at the key secondary endpoint, while the difference at end of treatment (week 132) was 2.6 (0.1–5.0) and the total eGFR slope difference was 1.4 mL/min/1.73 m²/year (0.5–2.3) (Heerspink 2026, PMID 42242268). The discrepancy between a non-significant endpoint at week 136 and a significant slope difference is exactly the surrogate-versus-endpoint problem this knowledge base tracks elsewhere: the off-treatment follow-up window returns some of the acute haemodynamic effect and moves the primary comparison across the significance threshold.

HIF prolyl hydroxylase inhibitors: pooled cardiovascular safety evidence

The class-level cardiovascular safety concern that shaped regulatory divergence has now been addressed by pooled long-term data. Across 25 randomized trials with ≥48 weeks' follow-up and 26,478 participants (13 trials, 13,230 participants on dialysis; 12 trials, 13,248 not on dialysis), there was no evidence of a difference in MACE — all-cause death, myocardial infarction or stroke — between HIF prolyl hydroxylase inhibitors and erythropoiesis-stimulating agents in dialysis-dependent CKD (RR 0.99, 95% CI 0.92–1.08) or non-dialysis CKD (RR 1.08, 0.95–1.22), nor versus placebo in non-dialysis CKD (RR 1.10, 0.96–1.27); individual MACE components and cardiovascular death agreed. In non-dialysis CKD, dialysis-access thrombosis, venous thromboembolism, infection and hyperkalaemia occurred more often with HIF-PHIs in placebo-controlled trials but not in ESA-controlled trials (Ha 2024, PMID 39186635).

The comparator asymmetry does not isolate a mechanism: placebo- and ESA-controlled trials enrolled different populations and differed in background anaemia treatment. It therefore cannot establish whether the excess thrombotic and infective events arise from haemoglobin correction, the drug mechanism or trial context.

Agent / class Best current evidence Status
Semaglutide, no diabetes Kidney composite HR 0.78 (0.63–0.96); eGFR +2.19 mL/min/1.73 m² at 104 wk if baseline eGFR <60 (Colhoun 2024, PMID 38796653) Signal extends beyond diabetes; low event count
GLP-1 RA on background SGLT2i MACE HR 0.77 (0.54–1.09) with vs 0.79 (0.71–0.87) without; kidney RR 0.79 (0.66–0.95) (Neuen 2024, PMID 39210781) Consistent but only 1,743 exposed
Zibotentan + dapagliflozin uACR reduced vs dapagliflozin alone at 12 weeks; fluid retention prespecified (Heerspink 2023, PMID 37931629) Phase 2b; outcome trial required
Atrasentan in IgA nephropathy eGFR difference 2.4 (−0.1 to 4.8) at wk 136; slope difference 1.4/yr (0.5–2.3) (Heerspink 2026, PMID 42242268) Disease-specific; endpoint narrowly missed
HIF-PHIs MACE RR 0.99 (0.92–1.08) vs ESA on dialysis; 1.08 (0.95–1.22) off dialysis (Ha 2024, PMID 39186635) Cardiovascular safety concern not confirmed

Dual incretin agonism: the first kidney comparison against an active GLP-1 comparator

Every GLP-1 kidney result discussed above compares an incretin agent against placebo. SURPASS-CVOT is the first to compare two incretin agents head to head with kidney endpoints. It randomized 13,299 people aged 40 or over with type 2 diabetes, atherosclerotic cardiovascular disease, HbA1c 7–10.5% and BMI ≥25 kg/m², at 640 sites in 30 countries, 1:1 to once-weekly tirzepatide up to 15 mg or dulaglutide 1.5 mg, double-blind and active-controlled; 2,948 had high-risk CKD at baseline. Annual visits measured serum creatinine, cystatin C and uACR, with eGFR calculated from the CKD-EPI creatinine–cystatin C equation. High-risk CKD was defined as eGFR ≥60 with uACR >300 mg/g, eGFR 45–<60 with uACR >30 mg/g, or eGFR <45. The prespecified exploratory kidney composite was time to first persistent macroalbuminuria, persistent ≥50% eGFR reduction, ESKD (eGFR <15 or chronic kidney replacement therapy), or kidney death (Zoungas 2026, PMID 42114520).

Two design choices matter when reading this result. Using the creatinine–cystatin C equation reduces dependence on creatinine alone in a weight-loss trial, and an active comparator makes the result a class-versus-class comparison rather than another placebo comparison.

The analyses are labelled prespecified but exploratory, so they generate rather than confirm a hypothesis about whether dual GIP/GLP-1 agonism differs from GLP-1 agonism alone on the kidney.

Decision and interpretation matrix

Dimension Question Guardrail
Diagnostic axis Cause + G category + A category Avoid treating eGFR as the diagnosis
Time axis Chronicity and trajectory Separate acute change from persistent disease
Risk axis Kidney failure + cardiovascular events + death Show competing events
Treatment axis Eligibility, absolute benefit, harm, burden Do not rank drugs by relative effect alone
Measurement axis Assay, equation, repeatability State what was actually measured
Equity axis Testing, referral, access, affordability Audit downstream care, not labels only
Patient axis Symptoms, function, life participation Include outcomes patients prioritize
Evidence axis RCT, cohort, model, guideline Do not collapse designs

Evidence ledger

This ledger makes the page’s evidentiary mix inspectable. It does not imply that every source answers every question.

PMID Record used Role and boundary
38785209 Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. (Perkovic 2024, PMID 38785209) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38914124 Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. (Mann 2024, PMID 38914124) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37952217 Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. (Neuen 2024, PMID 37952217) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
24206459 Bardoxolone methyl in type 2 diabetes and stage 4 CKD. (de Zeeuw 2013, PMID 24206459) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38490803 KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. (KDIGO CKD Work Group 2024, PMID 38490803) Guideline or commentary; recommendation evidence depends on its review.
38519239 Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. (Levin 2024, PMID 38519239) Guideline or commentary; recommendation evidence depends on its review.
11565518 Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. (Brenner 2001, PMID 11565518) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565517 Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. (Lewis 2001, PMID 11565517) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565519 The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. (Parving 2001, PMID 11565519) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
18707986 Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. (Mann 2008, PMID 18707986) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
24206457 Combined angiotensin inhibition for the treatment of diabetic nephropathy. (Fried 2013, PMID 24206457) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
32970396 Dapagliflozin in Patients with Chronic Kidney Disease. (Heerspink 2020, PMID 32970396) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
34619108 Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. (Heerspink 2021, PMID 34619108) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36331190 Empagliflozin in Patients with Chronic Kidney Disease. (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38061371 Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. (EMPA-KIDNEY Collaborative Group 2024, PMID 38061371) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30990260 Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. (Perkovic 2019, PMID 30990260) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
33264825 Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. (Bakris 2020, PMID 33264825) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
35023547 Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. (Agarwal 2022, PMID 35023547) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30697905 SGLT2 inhibitors and cardiovascular, renal and safety outcomes in T2D and CKD: meta-analysis. (Toyama 2019, PMID 30697905) Synthesis; heterogeneity and included-study definitions constrain transport.
36316605 SGLT2 inhibitors in advanced CKD: systematic review and meta-analysis. (Cao 2023, PMID 36316605) Synthesis; heterogeneity and included-study definitions constrain transport.
36927680 Finerenone outcomes in stage 4 CKD and type 2 diabetes. (Sarafidis 2023, PMID 36927680) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36272755 Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. (Rossing 2022, PMID 36272755) Guideline or commentary; recommendation evidence depends on its review.
33637203 Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. (Cheung 2021, PMID 33637203) Guideline or commentary; recommendation evidence depends on its review.
31533906 Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. (Agarwal 2019, PMID 31533906) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
40542996 Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. (Huang 2025, PMID 40542996) Synthesis; heterogeneity and included-study definitions constrain transport.
42567173 Semaglutide kidney outcomes pooled across SELECT, FLOW and SOUL. (Mann 2026, PMID 42567173) Synthesis; heterogeneity and included-study definitions constrain transport.
40470996 Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes (CONFIDENCE). (Agarwal 2025, PMID 40470996) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.

What can and cannot be concluded

  • Risk associations do not by themselves establish that changing the marker changes risk.
  • A relative effect must be paired with baseline risk, follow-up and the exact endpoint.
  • Albuminuria, acute eGFR change, chronic eGFR slope and kidney failure are not interchangeable.
  • Subgroup consistency is not evidence that every subgroup had adequate power.
  • Guideline recommendations combine evidence with values, feasibility, cost and service capacity.
  • Older adults require competing-mortality and treatment-burden framing.
  • Dialysis and transplantation comparisons are vulnerable to eligibility and immortal-time bias.
  • Modelled lifetime benefit is not a randomized observed benefit.
  • A biochemical response without a patient-important outcome remains a surrogate result.
  • This page is research synthesis, not individualized medical advice.

Research-design checklist

  • Define CKD cause, G category, A category and chronicity at baseline.
  • Report the creatinine or cystatin C equation and laboratory calibration.
  • Prespecify acute and chronic eGFR slopes when haemodynamic effects are expected.
  • Keep sustained GFR decline, kidney failure and replacement therapy separable.
  • Report absolute event risks, follow-up and confidence intervals with relative effects.
  • Treat death as a competing event where it can preclude kidney failure.
  • Measure hyperkalaemia, acute kidney injury and treatment discontinuation consistently.
  • Include symptoms, function, life participation and treatment burden.
  • Describe background RAS, SGLT2, MRA and GLP-1 therapy explicitly.
  • Prespecify albuminuria and cause strata without over-reading underpowered interactions.
  • Record screening, prescribing, persistence and monitoring as separate implementation steps.
  • Report representation, access and affordability variables needed for equity analysis.

Open questions

  • Does semaglutide protect kidneys in CKD without diabetes as a primary question rather than a pooled secondary one? The SELECT/FLOW/SOUL pooling includes participants without diabetes but was not designed to answer it (Mann 2026, PMID 42567173).
  • Is the FLOW benefit additive to SGLT2 inhibition? The baseline-SGLT2 comparison was not randomised and the subgroup held only 550 participants (Mann 2024, PMID 38914124).
  • What would a four-class strategy trial have to look like to be affordable and still powered for kidney failure? The lifetime estimate is actuarial (Neuen 2024, PMID 37952217) and the only randomized combination read-out covers two classes on albuminuria (Agarwal 2025, PMID 40470996). → OQ-1

  • After bardoxolone, what evidence would justify accepting an eGFR rise as a benefit signal rather than a warning (de Zeeuw 2013, PMID 24206459)?

  • Are GLP-1 and SGLT2 kidney effects additive? Consistency across baseline SGLT2 use rests on 1,743 exposed participants, too few to exclude a modest interaction (Neuen 2024, PMID 39210781).

  • Should atrasentan be considered effective in IgA nephropathy? The key secondary eGFR endpoint at week 136 gave 2.4 mL/min/1.73 m² (−0.1 to 4.8; p=0.057) while the on-treatment difference and total slope were both significant (Heerspink 2026, PMID 42242268).
  • Can endothelin antagonism be delivered without fluid retention by pairing with an SGLT2 inhibitor, and does the albuminuria reduction translate to hard outcomes (Heerspink 2023, PMID 37931629)?
  • Are the excess thrombotic and infective events with HIF-PHIs attributable to anaemia correction rather than the mechanism? They appear in placebo-controlled but not ESA-controlled trials (Ha 2024, PMID 39186635).

  • What is the evidence for GLP-1 receptor agonists in CKD stages 4–5 and on dialysis, where trial representation is near-absent (Natale 2025, PMID 39963952)?

  • Does dual GIP/GLP-1 agonism differ from GLP-1 agonism alone on kidney endpoints? SURPASS-CVOT provides the only head-to-head data, in prespecified but exploratory analyses (Zoungas 2026, PMID 42114520).

  • How much of the apparent kidney benefit in weight-loss drug trials is creatinine-based eGFR artefact from lean-mass loss? SURPASS-CVOT used the creatinine–cystatin C equation specifically to address this (Zoungas 2026, PMID 42114520); most earlier trials did not.

References

  1. Perkovic et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024;391(2):109-121. PMID 38785209
  2. Mann et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024;30(10):2849-2856. PMID 38914124
  3. Neuen et al. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. Circulation. 2024;149(6):450-462. PMID 37952217
  4. de Zeeuw et al. Bardoxolone methyl in type 2 diabetes and stage 4 CKD. N Engl J Med. 2013;369(26):2492-2503. PMID 24206459
  5. KDIGO CKD Work Group et al. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. PMID 38490803
  6. Levin et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. Kidney Int. 2024;105(4):684-701. PMID 38519239
  7. Brenner et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869. PMID 11565518
  8. Lewis et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. PMID 11565517
  9. Parving et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-878. PMID 11565519
  10. Mann et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. Lancet. 2008;372(9638):547-553. PMID 18707986
  11. Fried et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. PMID 24206457
  12. Heerspink et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. PMID 32970396
  13. Heerspink et al. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(11):743-754. PMID 34619108
  14. EMPA-KIDNEY Collaborative Group et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. PMID 36331190
  15. EMPA-KIDNEY Collaborative Group et al. Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. Lancet Diabetes Endocrinol. 2024;12(1):39-50. PMID 38061371
  16. Perkovic et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306. PMID 30990260
  17. Bakris et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. PMID 33264825
  18. Agarwal et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. PMID 35023547
  19. Toyama et al. SGLT2 inhibitors and cardiovascular, renal and safety outcomes in T2D and CKD: meta-analysis. Diabetes Obes Metab. 2019;21(5):1237-1250. PMID 30697905
  20. Cao H, et al. Effects of sodium-glucose co-transporter-2 inhibitors on kidney, cardiovascular, and safety outcomes in patients with advanced chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2023;60(3):325-335. PMID 36316605
  21. Sarafidis et al. Finerenone outcomes in stage 4 CKD and type 2 diabetes. Clin J Am Soc Nephrol. 2023;18(5):602-612. PMID 36927680
  22. Rossing et al. Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. Kidney Int. 2022;102(5):990-999. PMID 36272755
  23. Cheung et al. Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. Kidney Int. 2021;99(3):559-569. PMID 33637203
  24. Agarwal et al. Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. Lancet. 2019;394(10208):1540-1550. PMID 31533906
  25. Huang et al. Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. Drugs. 2025;85(8):1013-1031. PMID 40542996
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  28. Colhoun HM, et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat Med. 2024;30(7):2058-2066. PMID 38796653
  29. Neuen BL, et al. Cardiovascular, Kidney, and Safety Outcomes With GLP-1 Receptor Agonists Alone and in Combination With SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis. Circulation. 2024;150(22):1781-1790. PMID 39210781
  30. Natale P, et al. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2025;2(2):CD015849. PMID 39963952
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