Background

Cardiovascular and kidney outcomes trials of sodium–glucose co-transporter 2 inhibitors (SGLT2is) in

type 2 diabetes (T2D) have shown cardiorenal protection in high-risk groups, shaping current

treatment guidelines. However, it has been unclear how widely these benefits apply across broader

T2D populations.

Methods

In Phase 1, a systematic review and meta-analysis of observational studies was performed to explore

the association between SGLT2is and heart failure risk compared with other glucose-lowering drugs.

Searches were conducted in PubMed, EMBASE, CINAHL, and Web of Science.

In Phase 2, three cross-sectional studies were performed using the Oxford-Royal College of General

Practitioners (RCGP) Research and Surveillance Centre (RSC) database to examine factors associated

with SGLT2i prescribing and assess how representative cardiovascular and kidney outcomes trials are

to people with T2D and/or chronic kidney disease (CKD). A retrospective cohort study used the same

data source to investigate the effect of combining SGLT2is with glucagon-like peptide-1 receptor

agonists (GLP-1 RAs) on estimated glomerular filtration rate (eGFR).

Results

Phase 1: The review synthesised 43 studies (21 in meta-analyses). SGLT2is were associated with

reduced hospitalisation for heart failure overall, and in subgroups with and without baseline

cardiovascular disease (CVD). Absolute risk reductions were greater among those with established

CVD.

Phase 2: In the observational studies, people with eGFR ≥60 mL/min/1.73m² were more likely to be

prescribed SGLT2is than those with lower eGFR, while individuals with heart failure or CVD were less

likely to receive them. Trial eligibility criteria proved narrow: Cardiovascular outcomes trials applied

to only 7–27% of people with T2D, while kidney outcomes trials applied to fewer than 10% of

individuals with CKD. Combination therapy was associated with smaller declines in eGFR than GLP-1

RA monotherapy but provided no additional benefit over SGLT2i monotherapy.

Conclusions

Cardiorenal benefits of SGLT2is observed in RCTs are only applicable to subgroups with co-existing

CVD, high cardiovascular risk, or high-risk CKD. These effects are more pronounced in RCTs than in

real-world T2D populations. Observational studies provide essential real-world evidence to

complement RCTs and should inform future guideline development for T2D management.