Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Abstract

Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Keywords: GLP-1 receptor agonists, SGLT-2 inhibitors, Combination therapy, Metabolic outcomes, Cardiovascular outcomes, Renal outcomes

Core Tip: GLP-1 receptor agonist (GLP-1RA) plus SGLT-2 inhibitor (SGLT-2I) dual therapy causes a greater reduction in HbA1c, body weight, and systolic blood pressure (SBP), compared to either agent alone with similar adverse events. However, lowering of HbA1c, body weight, and SBP with combination therapy appeared to be less, nearly equal, and more than additive, respectively, compared to the sum of either agent alone. Our meta-analysis from five cardiovascular outcome trials suggests a similar reduction in major adverse cardiovascular events with dual therapy compared to GLP-1RA or SGLT-2I alone, but an additional benefit in heart failure hospitalization is likely. Future trials are needed to confirm these findings.