A meta-analysis shows robust improvements in cardiac and renal outcomes with SGLT-2 inhibitors, independent of GLP-1 agonist use.

Many clinical guidelines recom­mend sodium-­glucose co-trans­porter­-2 (SGLT-2) inhibitors or glucagon-­like peptide­1 (GLP­-1) receptor agonists for patients with type 2 diabetes, given that either drug class can improve various meaningful cardiovascular and renal outcomes in high-­risk patients. Because they have different mechanisms of action, one could hypothesise that combination therapy would provide additional benefit, but clinical trials have not specifically addressed this question. American Diabetes Association standards of care state that combination therapy ‘may be considered’ for patients with or at high risk for atherosclerotic cardiovascular disease or heart failure (Diabetes Care 2024; 47[Suppl 1]: S179­S218).

In this meta-­analysis of 12 rando­mised, placebo­controlled trials of SGLT­-2 inhibitors (involving 72,000 patients with diabetes), researchers evaluated whether beneficial effects were consistent among the 4% of patients who also took GLP-1 agonists. SGLT-­2 inhibitors (vs placebo) were associated with significantly less risk for major adverse cardiovascular events (hazard ratio [HR], 0.89), heart failure hospitalisation or cardio­ vascular-­related death (HR, 0.77) and chronic kidney disease progression (HR, 0.67), and slower estimated glomerular filtration rate decline (by 30%); magnitude of benefit was similar regardless of whether patients were taking GLP-­1 agonists at baseline or not. For most outcomes examined in this analysis, absolute differences between SGLT-­2 and placebo groups were about one to two fewer events per 100 patient-­years.

Comment: These results show that the impressive cardiometabolic benefits of SGLT­-2 inhibitors are independent of GLP-­1 agonist therapy. The analysis suggests that the effects of these drug classes might complement each other, but it does not prove an additive effect (because we do not know with certainty whether the 4% of patients who received both drugs were deriving independent benefit from the GLP-­1 agonists). Patients in this analysis were at high risk, most with established cardiac or renal disease. Given the high cost of these agents, I will continue to reserve combination therapy for my highest­ risk patients, who are most likely to benefit.

Sarah E. Post, MD, Lecturer in Medicine, Harvard Medical School; primary care physician and medical educator, Atrius Health, Boston, USA.

Apperloo iEM, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2024; 12: 545-557. Escobar Cervantes C. SGLT2 inhibitors and GLP-1 receptor agonists: the definitive combination? Lancet Diabetes Endocrinol 2024; 12: 507-508.