SGLT2 Inhibitors Beyond Diabetes: What the Evidence Shows for Cardiorenal Protection
A synthesis of 10 landmark trials enrolling over 40,000 patients examines whether SGLT2 inhibitors reduce heart failure events and slow kidney disease progression independently of glycaemic control.
This is an original evidence synthesis. See References for source studies.
One-Minute Takeaway
One-Minute Takeaway
- Strong evidence from multiple concordant RCTs supports SGLT2 inhibitors beyond diabetes for reducing heart failure hospitalisations and cardiovascular death across the full ejection fraction spectrum, with pooled hazard ratios ranging from 0.74 to 0.82 (Zannad et al. 2020 meta-analysis; DELIVER 2022).
- Renal protection appears consistent regardless of diabetes status — DAPA-CKD was stopped early for overwhelming efficacy, and EMPA-KIDNEY confirmed a 28% reduction in kidney disease progression among its 3,569 participants without diabetes.
- Benefits in non-diabetic subgroups were remarkably consistent with those in diabetic populations across all major trials, with no significant treatment-by-diabetes-status interactions detected.
- Important gaps remain: long-term safety data beyond 3 years in non-diabetic populations are limited, and specific glomerular disease subgroups (lupus nephritis, ANCA vasculitis) were excluded from the major CKD trials. Through 2025.
Why SGLT2 Inhibitors in Non-Diabetic Patients Matters
Heart failure affects over 64 million people globally, and chronic kidney disease is present in approximately 700 million individuals worldwide. For decades, the therapeutic landscape for these conditions — particularly heart failure with preserved ejection fraction — remained frustratingly limited. The emergence of SGLT2 inhibitors as agents with cardiorenal protective effects independent of glucose lowering has fundamentally altered this landscape.
What began as an unexpected finding in cardiovascular outcome trials designed for diabetes has sparked a paradigm shift. Multiple regulatory agencies now approve dapagliflozin and empagliflozin for heart failure and CKD regardless of diabetes status, and international guidelines position these agents as foundational therapy. This evidence review synthesises the data driving these changes.
What Evidence Was Reviewed
This synthesis draws on 10 randomised controlled trials and two prespecified meta-analyses that specifically enrolled or provided subgroup data on non-diabetic patients with heart failure or CKD. The evidence base spans reduced, mildly reduced, and preserved ejection fraction, as well as a broad range of kidney disease aetiologies. Collectively, these trials enrolled over 40,000 participants, with approximately half lacking diabetes at baseline.
| Study | Design | n | Population | Key Finding (Non-Diabetic Subgroup) | Quality |
|---|---|---|---|---|---|
| DAPA-HF (2019) | RCT | 4,744 | HFrEF ± diabetes | Consistent benefit regardless of diabetes; HR 0.74 (95% CI 0.65–0.85) for primary composite | High |
| EMPEROR-Reduced (2020) | RCT | 3,730 | HFrEF ± diabetes | 25% reduction in CV death/HF hospitalisation irrespective of diabetes; eGFR decline slowed | High |
| Zannad et al. MA (2020) | Meta-analysis | 8,474 | Pooled HFrEF | Pooled HR 0.74 (95% CI 0.68–0.82); no diabetes interaction; renal composite HR 0.62 | High |
| EMPEROR-Preserved (2021) | RCT | 5,988 | HFpEF (EF >40%) ± diabetes | 21% reduction in primary outcome; consistent in patients without diabetes | High |
| DELIVER (2022) | RCT | 6,263 | HFmrEF/HFpEF ± diabetes | HR 0.82 (95% CI 0.73–0.92); similar across diabetes subgroups | High |
| DAPA-CKD (2020) | RCT | 4,304 | CKD ± diabetes | HR 0.61 (95% CI 0.51–0.72) for primary renal composite; stopped early; NNT 19 | High |
| EMPA-KIDNEY (2023) | RCT | 6,609 | Broad CKD ± diabetes | 28% reduction in kidney progression; 3,569 participants without diabetes; stopped early | High |
| CREDENCE (2019) | RCT | 4,401 | Diabetic CKD only | Comparator trial — all diabetic; established renal class effect; stopped early | High |
| SOLOIST-WHF (2021) | RCT | 1,222 | Acute decompensated HF (diabetic) | Benefit in recently hospitalised HF; sotagliflozin; supports class effect across settings | Moderate |
| Vaduganathan et al. MA (2022) | Meta-analysis | ~21,900 | Pooled HF (all EF) | Consistent benefit across full EF spectrum; 37% reduction in kidney progression as class | High |
Key Findings: SGLT2 Inhibitors Beyond Diabetes in Heart Failure and CKD
Heart Failure With Reduced Ejection Fraction: Diabetes-Independent Protection
The two pivotal HFrEF trials — DAPA-HF and EMPEROR-Reduced — each enrolled approximately 50% of participants without diabetes and both reported remarkably consistent benefits across diabetes subgroups. The pooled meta-analysis by Zannad and colleagues demonstrated a 26% relative risk reduction in the composite of cardiovascular death or first heart failure hospitalisation (HR 0.74, 95% CI 0.68–0.82), with no significant interaction by diabetes status. Effect sizes for heart failure hospitalisation alone ranged from HR 0.67 to 0.70 across the two trials, and both reported slower eGFR decline in the SGLT2 inhibitor arms.
Notably, both trials required robust background guideline-directed medical therapy including beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid antagonists. The additive benefit of SGLT2 inhibition on top of this optimised regimen underscores that the mechanism of benefit extends well beyond diuresis or glucose lowering. A pooled analysis demonstrated a 14% reduction in cardiovascular death (HR 0.86, 95% CI 0.76–0.98), providing evidence that survival benefit exists alongside the well-established reduction in hospitalisations.
Extending the Benefit Across the Ejection Fraction Spectrum
The question of whether SGLT2 inhibitors protect patients with higher ejection fractions was addressed by EMPEROR-Preserved and DELIVER. Empagliflozin reduced the primary composite by 21% in HFpEF (HR 0.79, 95% CI 0.69–0.90), driven primarily by a 29% reduction in heart failure hospitalisation. The DELIVER trial confirmed this pattern with dapagliflozin, showing an 18% risk reduction (HR 0.82, 95% CI 0.73–0.92) in patients with EF above 40%. In both trials, the effects appeared consistent in patients with and without diabetes, with no significant treatment-by-subgroup interaction.
Pre-specified analyses from EMPEROR-Preserved stratified by ejection fraction showed benefit in both the truly preserved (EF ≥50%, HR 0.83) and mildly reduced (EF 41–49%, HR 0.71) subgroups. This matters clinically because HFpEF has historically lacked any mortality- or morbidity-reducing pharmacotherapy, and the diabetes-independent benefit means these agents can now be considered for the majority of HFpEF patients.
Subgroup analyses across DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER consistently showed that patients aged 75 years and older derived similar relative risk reductions as younger participants. DELIVER specifically examined patients with high frailty burden and polypharmacy (≥10 medications) without finding attenuation of benefit. The favourable safety profile — including minimal hypotension and no increased hypoglycaemia risk in non-diabetic patients — supports use even in older adults where medication burden is a concern.
Women comprised approximately 24% of HFrEF trial participants and 44% of HFpEF trial participants. The pooled meta-analysis of DAPA-HF and EMPEROR-Reduced found no significant treatment-by-sex interaction for the primary composite endpoint. In the DELIVER trial, 43.9% of participants were women, and benefits were consistent irrespective of sex. Given that HFpEF disproportionately affects women, the demonstrated efficacy in this population is particularly relevant. However, women remain underrepresented in HFrEF trials, and sex-specific response data warrant further investigation.
DAPA-CKD provided the first outcome data in non-diabetic CKD, including a pre-specified subgroup of 270 patients with IgA nephropathy who showed a significant reduction in kidney disease progression with no cases of ketoacidosis. EMPA-KIDNEY expanded this evidence substantially, enrolling 3,569 participants without diabetes and demonstrating a 29% relative risk reduction in kidney disease progression (HR 0.71, 95% CI 0.62–0.81) across multiple non-diabetic aetiologies. Secondary analyses showed broadly similar effects across glomerular diseases, hypertensive nephropathy, and other causes. Both trials excluded patients with polycystic kidney disease, lupus nephritis, and ANCA-associated vasculitis — populations where evidence remains absent.
Earlier SGLT2 inhibitor trials excluded patients with severely reduced kidney function. DAPA-CKD included 624 patients with eGFR below 30 mL/min/1.73 m², demonstrating consistent benefit. EMPA-KIDNEY substantially expanded this evidence with 2,282 patients (34.5%) having eGFR below 30. The meta-analysis of these trials supports organ-protective effects down to eGFR thresholds of 20–25 mL/min/1.73 m², challenging earlier prescribing restrictions. The initial mild dip in eGFR observed with treatment initiation is expected, reversible, and followed by long-term preservation of kidney function — analogous to the haemodynamic effect seen with ACE inhibitors.
Kidney Disease Progression: Protection Independent of Glucose Control
The renal evidence base is anchored by DAPA-CKD and EMPA-KIDNEY, both stopped early by independent data monitoring committees due to overwhelming efficacy. DAPA-CKD demonstrated a 39% relative risk reduction in its primary composite of sustained eGFR decline ≥50%, end-stage kidney disease, or death from renal or cardiovascular causes (HR 0.61, 95% CI 0.51–0.72), with a number needed to treat of only 19. EMPA-KIDNEY confirmed a 28% reduction in kidney disease progression across a broader CKD population. A subsequent meta-analysis of 13 trials involving over 90,000 participants found that SGLT2 inhibitors reduced kidney disease progression by 37%, acute kidney injury by 23%, and the composite of cardiovascular death or heart failure hospitalisation by 23% — all irrespective of diabetes status.
Quality & Consistency of Evidence
What the Evidence Does NOT Show
Despite the robust overall evidence base, several clinically important questions remain unanswered for SGLT2 inhibitors in non-diabetic populations.
Excluded kidney disease aetiologies: Patients with polycystic kidney disease, lupus nephritis, and ANCA-associated vasculitis were excluded from both DAPA-CKD and EMPA-KIDNEY. Whether SGLT2 inhibitors confer benefit in these immune-mediated or structural nephropathies cannot be inferred from the available data.
Long-term safety beyond 3 years: Median follow-up across the major trials ranged from 16 months to 2.4 years. Safety data specifically in non-diabetic populations extending beyond this timeframe are limited. While the short-to-medium term safety profile appears favourable, the consequences of chronic tubuloglomerular feedback alteration over decades remain unclear.
Optimal initiation timing: Most trials enrolled stable outpatients. SOLOIST-WHF demonstrated benefit with early inpatient initiation, but this trial was restricted to diabetic patients. Whether in-hospital initiation in acutely decompensated non-diabetic patients is safe and effective is an evolving area of investigation.
Comparative effectiveness between agents: Head-to-head trials comparing dapagliflozin, empagliflozin, and other SGLT2 inhibitors in non-diabetic cardiorenal disease do not exist. Indirect comparisons suggest a class effect, but definitive evidence of interchangeability is absent.
Practical Implications
Based on the current evidence, the following considerations emerge for clinicians managing non-diabetic patients with heart failure or CKD.
Concordant data from DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER provide evidence supporting SGLT2 inhibitor use in patients with heart failure regardless of EF or diabetes status. The 2022 AHA/ACC/HFSA guidelines assign a Class I recommendation for HFrEF and a Class 2a recommendation for HFmrEF/HFpEF.
Combined evidence from DAPA-CKD and EMPA-KIDNEY supports initiation at eGFR levels as low as 20 mL/min/1.73 m². The anticipated initial eGFR dip is haemodynamic, typically reversible within weeks, and should not prompt discontinuation. Once initiated, continuation is supported even if eGFR declines below the initiation threshold.
Unlike many heart failure medications, both dapagliflozin and empagliflozin are administered at a fixed 10 mg daily dose without need for titration. Trial data suggest this simplicity is safe across a broad range of ages, kidney function levels, and degrees of polypharmacy.
The available evidence indicates that the risk of euglycaemic ketoacidosis and hypoglycaemia is extremely low in non-diabetic patients. Genital mycotic infections remain the most common adverse effect. Volume depletion and hypotension were not significantly increased compared with placebo across the major trials.
Evidence Grade & Bottom Line
Evidence Grade: Strong
Multiple large, well-designed RCTs with concordant results across agents, populations, and endpoints. Confidence in the estimate is high for heart failure outcomes and kidney disease progression in non-diabetic patients. This grade reflects evidence unlikely to change substantially with further research for the primary cardiorenal endpoints.
A “Strong” evidence grade indicates that the body of evidence is sufficiently robust that clinicians can apply these findings with confidence. The diabetes-independent benefit of SGLT2 inhibitors in heart failure and CKD is supported by the highest level of randomised evidence, and the consistency across multiple agents suggests a class effect. Remaining uncertainty relates to specific subpopulations and long-term outcomes rather than the core treatment question.
- SGLT2 inhibitors reduce heart failure hospitalisations and slow CKD progression irrespective of diabetes status — a class effect supported by 10+ major RCTs
- Benefits extend across the full ejection fraction spectrum (HFrEF, HFmrEF, and HFpEF) and down to eGFR 20 mL/min/1.73 m²
- A pooled cardiovascular mortality reduction of 14% is suggested in HFrEF but not confirmed in HFpEF
- Fixed dosing, favourable safety profile, and no glycaemic risk in non-diabetic patients lower barriers to initiation
- Gaps persist for specific glomerular diseases (lupus nephritis, ANCA vasculitis, PKD), optimal inpatient initiation timing in non-diabetic acute HF, and long-term outcomes beyond 3 years
Article Information
For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.
References
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