SGLT-2 Inhibitors and GLP-1 Receptor Agonists as Combination Therapy in Type 2 Diabetes

The pharmacologic management of type 2 diabetes prioritises sodium-glucose cotransporter 2 (SGLT-2) inhibitors or glucagon-like peptide 1 (GLP-1) receptor agonists for their demonstrated cardiovascular benefits in individuals with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors, chronic kidney disease, and heart failure. However, while current guidelines recommend these drug classes alone, combination therapy is not explicitly advocated. Herein we summarise the rationale and available evidence in support for combination therapy.

Evidence suggests that combining SGLT-2 inhibitors and GLP-1 receptor agonists improves metabolic outcomes, including HbA_1c, body weight, and blood pressure. More importantly, combination therapy can offer potential advantages for addressing residual cardiovascular risk, particularly in high-risk populations. Data from cardiovascular outcomes trials and real-world studies demonstrate consistent benefits of combination therapy across diverse subpopulations, including those with established atherosclerotic cardiovascular disease or chronic kidney disease. However, robust evidence remains limited for individuals at low cardiovascular risk, where therapy should primarily focus on metabolic goals. Of note, combination therapy faces significant barriers, including safety concerns in older or frail individuals, underutilisation in disadvantaged populations, while economic challenges may further hinder the accessibility of these therapies. Upfront combination therapy with both SGLT-2 inhibitors and GLP-1 receptor agonists could further reduce cardiovascular risk in people with type 2 diabetes, although it is crucial to pare down cost and disparities to access to maximise widespread benefits at population level.