SGLT-2 Inhibitors and Risk of 59 Long-Term Health Conditions, Hospitalization, and Mortality.

BACKGROUND:Type 2 diabetes mellitus (T2DM) is often the first condition on the pathway to patients developing multiple long-term conditions (MLTCs). The impact of sodium-glucose cotransporter 2 inhibitors (SGLT-2i), a key T2DM treatment, on hospitalization and MLTC progression remains uncertain. METHODS:In this comparative effectiveness study, we emulated a target trial using linked primary care, hospital, and mortality records in England (2012-2023). Adults aged ≥40 years with T2DM initiating SGLT-2i or dipeptidyl peptidase-4 inhibitors (DPP-4i) were included (n = 364 522). Outcomes included all-cause mortality, first hospitalization, number of hospitalizations, and incidence of 59 prespecified long-term conditions across 17 organ systems. Weighted Cox proportional hazards and negative binomial regression models were used to estimate adjusted hazard ratios (aHRs) or adjusted mean differences (aMDs), with 95% CIs and Benjamini-Yekutieli correction for multiple testing. FINDINGS:Compared with DPP-4i, SGLT-2i use was associated with lower risks of all-cause mortality (aHR 0.73, 95% CI 0.71-0.75), first hospitalization (aHR 0.86, 95% CI 0.85-0.87), and number of hospitalizations (aMD -0.36, 95% CI -0.38 to -0.34; all P < .001). SGLT-2i initiators had reduced risks for 28 conditions, including dementia, cancer, metabolic dysfunction-associated steatotic liver disease, diabetic foot ulcer, epilepsy, and rheumatoid arthritis. Increased risks were observed for four conditions, including candidiasis and diabetic ketoacidosis. INTERPRETATION:SGLT-2i use in T2DM was associated with significant reductions in mortality, hospitalization, and MLTC burden. The broad protective effects across multiple organ systems highlight the potential of SGLT-2i to provide a holistic therapeutic strategy in the management of diabetes and its multisystem complications.