Efpeglenatide and Clinical Outcomes with and without Concomitant Sodium-Glucose Co-Transporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial

Abstract

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) both reduce cardiovascular (CV) events among patients with type 2 diabetes. However, no CV outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial reported that once weekly injections of the GLP-1 RA efpeglenatide (vs. placebo) reduced major adverse cardiovascular events (MACE); MACE, coronary revascularization or unstable angina hospitalization (expanded MACE); a renal composite outcome; and MACE or death in people with type 2 diabetes and CV and/or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among GLP-1 RA CV outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Methods: Cardiovascular and renal outcomes were analyzed using Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed using a mixed-effects models for repeated measures that also included an interaction term. Results: The effect (hazard ratio [95% confidence interval]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors, respectively, on MACE (0.74 [0.58- 0.94] and 0.70 [0.37- 1.30]), expanded MACE (0.77 [0.62- 0.96] and 0.87 [0.51- 1.48]), renal composite (0.70 [0.59- 0.83] and 0.52 [0.33- 0.83]), and MACE or death (0.74 [0.59- 0.93] and 0.65 [0.36- 1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). Efpeglenatide's reduction of blood pressure, body weight, low density lipoprotein cholesterol and urinary albumin:creatinine ratio also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P ≥0.08). Finally, adverse events did not differ by baseline SGLT2 inhibitor use. Conclusions: The efficacy and safety of efpeglenatide appear independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and GLP-1 RA therapy in type 2 diabetes.