Highlights
• In a pooled, time-updated analysis of five randomized, placebo‑controlled trials (n=26,946), 5.2% of participants experienced eGFR deterioration to <25 ml/min/1.73 m2 and 2.3% to <20 ml/min/1.73 m2 during follow-up.
• Severe eGFR deterioration during follow‑up was independently associated with nearly double the risk of subsequent heart‑failure hospitalization or cardiovascular death, major atherothrombotic events, and all‑cause mortality.
• Allocation to SGLT2 inhibitors both reduced the probability of severe eGFR deterioration and delivered cardiovascular and survival benefits that were preserved irrespective of whether patients experienced severe eGFR decline (interaction p>0.1 for all outcomes).
Background
Patients with overlapping cardiovascular, kidney and metabolic (CKM) conditions are at particularly high risk of adverse outcomes. Declining kidney function, quantified by estimated glomerular filtration rate (eGFR), amplifies cardiovascular risk and complicates therapeutic decision‑making. Sodium‑glucose co‑transporter 2 inhibitors (SGLT2i) have transformed management across diabetes, heart failure and chronic kidney disease (CKD), demonstrating benefits on cardiovascular events, heart‑failure hospitalization, progression of kidney disease, and mortality in multiple randomized trials (EMPA‑REG OUTCOME, CANVAS, CREDENCE, DAPA‑HF, DAPA‑CKD, EMPEROR‑Reduced/Preserved, EMPA‑KIDNEY).
Nevertheless, the clinical question of whether SGLT2i retain efficacy when patients later experience severe eGFR deterioration during follow‑up — and whether SGLT2i affect the probability of such severe declines — has important implications for initiation, continuation and safety in patients with progressive CKD or those who have large eGFR dips after treatment initiation.
Study design and methods
The pooled analysis by Ferreira et al. combined individual trial data from five major placebo‑controlled randomized trials: EMPEROR‑Preserved, EMPEROR‑Reduced, EMPA‑REG OUTCOME, CANVAS‑R, and CREDENCE. These trials enrolled patients across the cardio‑renal‑metabolic spectrum (heart failure with reduced and preserved ejection fraction, type 2 diabetes with cardiovascular risk, and albuminuric CKD). Time‑updated Cox models stratified by study were used to evaluate associations between severe eGFR deterioration (defined as reaching eGFR <25 ml/min/1.73 m2 and a secondary threshold <20 ml/min/1.73 m2 during follow‑up) and subsequent clinical outcomes. Outcomes included the composite of heart‑failure hospitalization or cardiovascular death, atherothrombotic major adverse cardiovascular events (MACE: cardiovascular death, nonfatal stroke, nonfatal myocardial infarction), and all‑cause mortality. The models adjusted for baseline risk factors and used time‑updated exposure for eGFR status; interaction tests assessed whether treatment effects differed according to occurrence of severe eGFR decline.
Follow‑up metrics reported: median time to eGFR deterioration was 17 months and the overall median follow‑time was 29 months.
Key findings
Population and incidence of renal deterioration: Among 26,946 randomized participants, 1,392 (5.2%) reached eGFR <25 ml/min/1.73 m2 during follow‑up; 613 (2.3%) reached the more stringent threshold of <20 ml/min/1.73 m2.
Baseline predictors of severe eGFR decline: Lower baseline eGFR and higher albuminuria were the strongest independent predictors of progressing to severe eGFR deterioration. Importantly, randomization to SGLT2i was independently associated with a lower probability of reaching the severe eGFR thresholds during follow‑up.
Impact of eGFR deterioration on outcomes: The occurrence of severe eGFR decline was independently associated with approximately a twofold higher risk of subsequent adverse outcomes. Specifically, after adjusting for confounders, patients who reached eGFR <25 ml/min/1.73 m2 had a near‑doubling of risk for the composite of heart‑failure hospitalization or cardiovascular death, the MACE composite, and all‑cause mortality compared with patients who did not reach that threshold. Effect sizes were directionally consistent for the <20 ml/min/1.73 m2 subgroup, though event counts were smaller.
SGLT2i treatment effects preserved despite eGFR decline: Crucially, benefit from SGLT2 inhibitors on cardiovascular endpoints and mortality was preserved irrespective of whether participants experienced severe eGFR deterioration during follow‑up. Tests for interaction were nonsignificant (interaction p>0.1 for all outcomes), indicating that the relative risk reductions conferred by SGLT2i applied similarly in patients with and without severe declines in eGFR.
Treatment discontinuation: Participants who experienced severe eGFR deterioration were more likely to permanently discontinue randomized treatment. However, discontinuation rates did not differ significantly between SGLT2i and placebo arms, suggesting that the decision to stop therapy was related to worsening kidney function rather than a drug‑specific adverse effect signal in these trials.
Absolute and relative benefits — practical interpretation
The pooled analysis demonstrates two clinically relevant points. First, severe renal deterioration during follow‑up identifies a subgroup at markedly higher event risk; second, SGLT2 inhibitors both reduce the risk of progressing to severe eGFR decline and retain cardiovascular and survival benefits even among individuals who do progress to very low eGFR levels. In practical terms, clinicians should not assume loss of SGLT2i benefit if a patient later experiences kidney function decline; conversely, SGLT2i may help prevent the transition to higher‑risk kidney stages.
Safety signals and practical considerations
These trial datasets did not indicate an excess of permanent treatment discontinuation attributable specifically to SGLT2 inhibitors compared with placebo in patients who experienced eGFR deterioration. This aligns with prior trial observations that although an acute eGFR dip may occur after SGLT2i initiation, the long‑term trajectory typically favors preserved eGFR and reduced risk of progression to kidney failure. Nevertheless, clinicians should monitor renal function after initiation and during follow‑up, be alert for volume depletion and other contributory factors (e.g., diuretic dose, hypotension), and individualize decisions about continuing therapy when eGFR reaches very low levels, taking into account indications such as heart failure where continued benefit is documented even at lower eGFR ranges.
Mechanistic insights
SGLT2 inhibitors exert multiple renal and systemic effects that plausibly underlie their dual renal‑cardiovascular benefits: improvement in intraglomerular hemodynamics via restoration of tubuloglomerular feedback (reducing hyperfiltration), natriuresis leading to reduced preload/afterload, improved cardiac energetics and reduction of myocardial stress, and favorable metabolic and anti‑inflammatory effects. These mechanisms are consistent with findings that SGLT2i reduce albuminuria and slow eGFR decline and provide heart‑failure benefits that are at least partly independent of baseline eGFR.
Expert commentary and guideline alignment
The findings reinforce current guideline trends that favor broader and earlier use of SGLT2 inhibitors across CKM conditions. KDIGO and major cardiology societies now recommend SGLT2i for many patients with CKD and for those with heart failure, with less restrictive eGFR thresholds than historically used. The pooled analysis supports continuation of SGLT2i when feasible and clinically appropriate, even when renal function declines into severe ranges — a practical consideration echoed in recent consensus statements and trial subanalyses (for example, benefits in DAPA‑HF and EMPEROR trials were observed across eGFR subgroups).
Limitations and generalizability
Several caveats should be noted. The pooled cohort comprises randomized trial populations that may differ from real‑world patients (trial inclusion/exclusion criteria, closer monitoring). Event counts at very low eGFR thresholds were relatively small, particularly for the <20 ml/min/1.73 m2 subgroup, which limits precision for subgroup effect estimates. Time‑updated modeling mitigates immortal time bias but cannot eliminate all residual confounding. Finally, the trials included different SGLT2 agents and populations; while stratification by study was used, agent‑specific or indication‑specific nuances may exist.
Clinical implications and practical recommendations
1) Initiate SGLT2 inhibitors in eligible patients with diabetes, CKD, or heart failure according to current guideline indications, as they reduce risk of cardiovascular events, heart‑failure hospitalization and progression of kidney disease.
2) Do not reflexively discontinue SGLT2 inhibitors solely because a patient subsequently reaches eGFR <25 or <20 ml/min/1.73 m2. The pooled evidence shows preserved relative benefits and suggests that continuation is reasonable when clinical circumstances permit, particularly for heart‑failure indications.
3) Monitor renal function after initiation and during therapy. Expect an initial eGFR dip in some patients; differentiate expected hemodynamic changes from acute kidney injury due to other causes (hypovolemia, nephrotoxic agents, obstruction).
4) Optimize concomitant therapies (RAAS blockade where appropriate, diuretic adjustment) and manage volume status and blood pressure to reduce reversible contributors to eGFR decline and to permit continuation of disease‑modifying treatments.
Conclusion
The pooled analysis by Ferreira et al. provides reassuring and actionable evidence: severe eGFR deterioration during follow‑up identifies patients at markedly higher cardiovascular and mortality risk, but SGLT2 inhibitors both reduce the probability of such deterioration and retain cardiovascular and survival benefits even when severe kidney decline occurs. These findings support continued, guideline‑concordant use of SGLT2 inhibitors across the CKM spectrum, careful renal monitoring, and individualized decision‑making when kidney function reaches advanced stages.
References
1. Ferreira JP, Marques P, Anker SD, Butler J, Filippatos G, Sharma A, Vasques‑Nóvoa F, Mendonça L, Neves JS, Packer M, Zannad F. Sodium‑glucose co‑transporter 2 inhibitors in severe estimated glomerular filtration rate deterioration across cardiovascular‑kidney‑metabolic conditions: A pooled analysis of randomized trials. Eur J Heart Fail. 2025 Nov 9. doi: 10.1002/ejhf.70093. Epub ahead of print. PMID: 41206806.
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3. Neuen BL, Young T, Heerspink HJL, et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295‑2306.
4. McMurray JJV, Solomon SD, Inzucchi SE, et al.; DAPA‑HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995‑2008.
5. Heerspink HJL, Stefánsson BV, Correa‑Rotter R, et al.; DAPA‑CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436‑1446.
6. Heerspink HJL, Parving H‑H, de Zeeuw D. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752‑772.
7. KDIGO 2022 Clinical Practice Guideline for Management of Diabetes in CKD. Kidney Int. 2022;102(Suppl):S1‑S127.
8. Packer M, Anker SD, Butler J, et al.; EMPEROR‑Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413‑1424.
9. Anker SD, Butler J, Filippatos G, et al.; EMPEROR‑Preserved Trial Investigators. Empagliflozin in heart failure with preserved ejection fraction. N Engl J Med. 2021;385:1451‑1461.
10. Wiviott SD, Raz I, Bonaca MP, et al.; CANVAS Program Collaborative Group. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347‑357.
Note: Selected key trials and guideline documents are cited to contextualize the pooled analysis findings and to aid clinicians in interpretation and application.