• Combination therapy with an SGLT2 inhibitor and GLP-1 may reduce cardiovascular and renal risk more than monotherapy.
• The European Society of Cardiology recommends combination therapy for people at high CV risk.

PHILADELPHIA — Using a GLP-1 receptor agonist in combination with an SGLT2 inhibitor may provide additive cardiovascular and renal benefits for people with type 2 diabetes, according to a speaker at the Heart in Diabetes CME Conference.

Silvio E. Inzucchi, MD, medical director at the Yale Diabetes Center and a Healio | Endocrine Today Editorial Board Member, said there will likely never be a formal trial conducted assessing CV or kidney outcomes for adults receiving a combination SGLT2 inhibitor and GLP-1. However, Inzucchi said, data from observational studies and other trials may provide insight into the potential effects the two classes of drugs may have on one another.

A systematic review and meta-analysis of 18 cohort studies published in Diabetologia in 2025 found adults with type 2 diabetes who used an SGLT2 inhibitor and GLP-1 in combination had lower risk for major adverse CV events (RR = 0.56; 95% CI, 0.43-0.71) and all-cause mortality (RR = 0.5; 95% CI 0.4-0.63) than adults who received monotherapy. Inzucchi said these point estimates are larger than would be expected based on trial data assessing the individual effects of these medications, suggesting potential synergistic effects. An important caveat, however, is that such real-world data may exaggerate the benefits due to unaccounted confounders, according to Inzucchi.

Meta-analyses and trials have shown that adding SGLT2 inhibitors to background GLP-1 therapy or adding a GLP-1 to background SGLT2 inhibitor therapy likely have additive CV benefits. The SMART-C meta-analysis published in The Lancet Diabetes & Endocrinology in 2024 found that trial participants with diabetes who were randomly assigned to an SGLT2 inhibitor experienced a similar reduction in CV and CKD risk regardless of whether they were using a GLP-1 at baseline.

“The SGLT2 or the GLP-1 is really not affected by the presence of the opposite drug,” Inzucchi told Healio. “Statistically, that suggests that the benefits are going to be additive.”

In data from the FLOW trial published in Nature Medicine, however, once-weekly injectable semaglutide 1 mg (Ozempic, Novo Nordisk) appeared to provide no additional benefit on the primary CKD outcome in that trial when added to patients already taking an SGLT2 inhibitor, in contrast to SGLT2 inhibitor-naive patients. Improvement in the slope of the estimated glomerular filtration rate, a marker of decline in kidney function, seemed more similar.

In a systematic review of three GLP-1 trials, including FLOW, published in Circulation, risk for CV events was not affected by the presence or absence of SGLT2 inhibitors at baseline, suggesting additive benefits. However, both chronic kidney disease progression and change in estimated glomerular filtration rate slope outcomes were not improved with the GLP-1 in those already on an SGLT2. Inzucchi said data on the additive benefit of a GLP-1 during established SGLT2 inhibitor therapy is not as robust for kidney outcomes as it is for CV outcomes.

“It’s interesting that there’s this seeming dichotomy between the potential additive benefits of GLP-1s and SGLT2s on the heart and on the kidney,” Inzucchi said. “The precise sequence of combined therapy may in part influence the study findings.”

Several guidelines now recommend using a GLP-1 or SGLT2 in patients with type 2 diabetes at high CV risk. The American Diabetes Association Standards of Care, for example, advised using either class of medication to reduce CVD or CKD risk for people with type 2 diabetes, with a preference for SGLT2s in CKD. Kidney Disease: Improving Global Outcomes (KDIGO) recommends adding a GLP-1 to SGLT2 inhibitor therapy, but only if necessary to achieve a patient’s glycemic target. Inzucchi said, in contrast, the European Society of Cardiology was the first to recommend early combination of a GLP-1 and SGLT2 among people with type 2 diabetes with or at high risk for CVD.

“The best foundational therapy for type 2 diabetes, particularly those at high CV risk, would appear to be, from the outset, an SGLT2 inhibitor and a GLP-1 receptor agonist,” Inzucchi said.

Silvio E. Inzucchi, MD, is professor of medicine and clinical chief of the section of endocrinology at Yale University, medical director at the Yale Diabetes Center and a Healio | Endocrine Today Editorial Board Member. Inzucchi can be reached at endocrinology@healio.com.