SGLT Inhibitors in Heart Failure: Benefits Across Diabetes Status and Ejection Fraction

TheBrief:

Recent studies show that SGLT inhibitors can help treat heart failure in people with or without diabetes, regardless of their ejection fraction. Their main benefit is reducing heart failure events and hospitalizations. However, their effect on reducing the risk of death is smaller. These medicines are generally safe, but treatment should be tailored to each patient, especially with sotagliflozin, which works through two different mechanisms.

A broad benefit driven by fewer heart failure events

The updated evidence comes from systematic reviews and randomized trials evaluating SGLT2 inhibitors, along with sotagliflozin, which blocks both SGLT1 and SGLT2. The evidence now covers a much broader range of heart failure patients than the earlier studies that focused mainly on type 2 diabetes or reduced ejection fraction.

The established quantitative benchmark is a 2022 collaborative meta-analysis of five placebo-controlled trials involving 21,947 participants. Across the trials, SGLT inhibition reduced the composite of cardiovascular death or heart failure hospitalization by 23% relative to placebo, with a hazard ratio of 0.77 (95% CI, 0.72-0.82). First heart failure hospitalization fell by 28% (HR, 0.72; 95% CI, 0.67-0.78).

Mortality effects were more modest. Cardiovascular death was reduced by 13% (HR, 0.87; 95% CI, 0.79-0.95), while all-cause mortality had a hazard ratio of 0.92 (95% CI, 0.86-0.99). These results position prevention of worsening heart failure—not a large mortality reduction—as the most consistent class-wide benefit.

The major trials also show why ejection fraction and diabetes status are no longer reliable boundaries for benefit. In DAPA-HF, dapagliflozin reduced worsening heart failure or cardiovascular death among patients with reduced ejection fraction, including those without diabetes. EMPEROR-Reduced produced a similar result with empagliflozin. EMPEROR-Preserved and DELIVER subsequently extended the finding into mildly reduced and preserved ejection fraction.

The table should not be read as a head-to-head comparison. Trial populations, endpoint definitions, follow-up and statistical approaches differed, particularly because SOLOIST-WHF counted total events and urgent heart failure visits rather than only time to a first event.

How the evidence was assembled

The updated study is a systematic review and meta-analysis rather than a new randomized trial. Such analyses improve precision by combining event counts across studies and can test whether results remain consistent across clinically important subgroups. Their conclusions, however, remain dependent on the design and quality of the included trials.

The evidence is predominantly drawn from randomized, placebo-controlled outcome trials conducted in patients receiving background heart failure care. The major programs enrolled patients across reduced, mildly reduced and preserved ejection fraction, with and without type 2 diabetes. Most tested dapagliflozin or empagliflozin; SOLOIST-WHF supplied evidence for sotagliflozin after worsening heart failure in patients with diabetes.

That distinction matters. Sotagliflozin’s intestinal SGLT1 inhibition may alter postprandial glucose absorption and adds gastrointestinal effects not characteristic of selective SGLT2 inhibition. SOLOIST-WHF also stopped early after loss of funding, limiting follow-up and precision despite a favorable primary result. It should therefore strengthen the overall concept of SGLT inhibition without being treated as proof that all agents are interchangeable.

Applying the findings across phenotypes

For practice and policy, the evidence supports SGLT inhibition as a foundational heart failure strategy across the ejection-fraction spectrum. The relative reduction in heart failure events has been broadly consistent, although absolute benefit still depends on baseline risk. A recently hospitalized patient may avoid more events per 100 people treated than a stable outpatient even when relative effects are similar.

Diabetes is not required for the heart failure benefit of selective SGLT2 inhibitors. DAPA-HF and the empagliflozin program found no persuasive evidence that diabetes status materially modified cardiovascular efficacy. The mechanism in heart failure is therefore not adequately explained by glucose lowering alone.

Ejection fraction changes the surrounding therapeutic landscape more than it changes the SGLT signal. In reduced ejection fraction, SGLT2 inhibitors sit alongside several other therapies with survival and hospitalization benefits. In preserved ejection fraction, where fewer treatments have consistently reduced clinical events, their effect on worsening heart failure carries particular weight.

Safety still requires clinical context. Genital mycotic infection, volume depletion and an initial decline in estimated glomerular filtration rate are recognized considerations with SGLT2 inhibition. Diabetic ketoacidosis is uncommon but clinically serious and may occur without marked hyperglycemia, particularly during acute illness, prolonged fasting or severe insulin deficiency. Sotagliflozin additionally produced more diarrhea in SOLOIST-WHF, consistent with SGLT1 inhibition.

These risks do not erase the cardiovascular benefit, but they argue against treating “class effect” as meaning identical tolerability. Renal function, blood pressure, volume status, diabetes treatment and vulnerability to infection or ketoacidosis remain relevant when translating pooled findings into care.

Limits of the class-wide conclusion

Meta-analysis can establish consistency more convincingly than equivalence. The trials did not directly compare dapagliflozin, empagliflozin and sotagliflozin, and substantially less outcome evidence is available for dual SGLT1/2 inhibition. Differences among drugs could be obscured when results are pooled.

Endpoints and follow-up also varied. Some studies counted first hospitalizations, others recurrent events or urgent visits, and mortality analyses had fewer events than hospitalization analyses. Trial participants may not represent people with very low blood pressure, recurrent ketoacidosis, advanced frailty or unstable kidney function, who are often excluded or underrepresented.

The supplied updated PubMed record is dated July 20, 2026. Its pooled numerical estimates and complete study-level methods were not independently available during drafting; quantitative claims here therefore come from the cited randomized trials and the independently indexed five-trial collaborative meta-analysis.

Questions clinicians ask

Does a patient need diabetes to benefit?

No. Randomized trials of dapagliflozin and empagliflozin found reductions in heart failure outcomes among participants with and without type 2 diabetes. Diabetes remains relevant to ketoacidosis, glucose-lowering therapy and monitoring, but it is not a prerequisite for the demonstrated heart failure effect.

Is the evidence equally strong at every ejection fraction?

The direction of benefit is consistent from reduced through preserved ejection fraction, particularly for heart failure hospitalization or worsening heart failure. Mortality evidence is stronger in aggregate than within preserved-ejection-fraction trials, where fewer deaths and smaller treatment effects make drug-specific mortality conclusions less certain.

Does sotagliflozin offer an advantage over selective SGLT2 inhibitors?

No head-to-head outcome trial establishes superiority. SOLOIST-WHF supports sotagliflozin after worsening heart failure in patients with type 2 diabetes, but early termination, shorter follow-up and its distinct recurrent-event endpoint limit comparisons with dapagliflozin or empagliflozin.

Which safety issues can change the risk-benefit assessment?

Volume depletion, genital infection, kidney-function changes and ketoacidosis warrant attention with SGLT2 inhibition. Sotagliflozin also has a gastrointestinal tolerability consideration because diarrhea occurred more often in SOLOIST-WHF. Trial averages cannot substitute for assessment of volume status, renal function, acute illness and diabetes-related ketoacidosis risk.

Questions people ask

Can SGLT2 inhibitors help people with heart failure who do not have diabetes?

Yes. Clinical trials have shown heart failure benefits with dapagliflozin and empagliflozin in patients both with and without type 2 diabetes.

Do these medicines mainly work by lowering blood sugar?

No. Their heart failure benefits are not limited to glucose lowering. The clinical effects seen in people without diabetes support a broader cardiovascular and heart failure role.

Will these medicines completely prevent heart failure hospitalization?

No. They reduce the risk, but they do not eliminate it. Heart failure remains a chronic condition that usually requires a broader treatment plan, regular follow-up and management of other risk factors.

What should patients watch for during treatment?

Symptoms of dehydration, genital infections, severe illness or possible ketoacidosis should be taken seriously. Patients should follow their clinician’s instructions about medicines during acute illness, fasting or other situations that may increase treatment-related risks.

References

1. Efficacy and safety of SGLT2 inhibitors and sotagliflozin in heart failure: updated systematic review and meta-analysis — PubMed, 2026 2. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials — The Lancet, 2022 3. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction — The New England Journal of Medicine, 2019 4. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure — The New England Journal of Medicine, 2020 5. Empagliflozin in Heart Failure with a Preserved Ejection Fraction — The New England Journal of Medicine, 2021 6. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction — The New England Journal of Medicine, 2022 7. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure — The New England Journal of Medicine, 2021