Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis

Aim: To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease.Methods: We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs).Results: We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate.Conclusions: The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.