The combination of glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter-2 inhibitors: a narrative review of existing meta-analysis

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have profoundly reshaped the therapeutic landscape of type 2 diabetes mellitus (T2DM). In this narrative review, we critically appraise the published literature on the combined effects of these two classes on cardiovascular outcomes, heart failure, and kidney disease. Randomized controlled trials indicates that combination therapy achieves greater reductions in HbA1c compared with either agent alone. Meta-analyses demonstrate that both GLP-1RAs and SGLT2i reduce the risk of major adverse cardiovascular events (MACE) to a comparable extent, while SGLT2i provide superior benefits in mitigating hospitalization for heart failure and slowing chronic kidney disease progression. However, cardiovascular outcome trials (CVOTs) have not demonstrated a synergistic or additive protective effect of combined therapy on MACE or renal endpoints. In contrast, real-world evidence suggests incremental benefits across MACE, heart failure, and renal outcomes, supporting the hypothesis that complementary mechanisms of action may translate into broader protection in clinical practice. In this context, the aim of the present work is to summarize the existing meta-analyses that have evaluated both real-world studies and randomized controlled trials assessing the combination therapy of GLP-1 receptor agonists and SGLT2 inhibitors.Globally, GLP-1RAs and SGLT2i should be regarded as complementary rather than alternative therapeutic strategies. Randomized evidence supports the individual efficacy of each class and real-world data increasingly endorse their combined use to optimize cardiovascular and renal protection in patients with T2DM.