ADA 81st Symposium: Cardiovascular and Kidney Outcomes in Efpeglenatide

With the introduction of this glucagon-like peptide-1 receptor agonist (GLP-1 RA), efpeglenatide, could we see new cardiovascular and renal benefits for patients with type 2 diabetes? 

Patients with type 2 diabetes are at a higher risk of developing other complications if their HbA1c and glucose levels remain above goal. In addition, common comorbidities accompanying diabetes are cardiovascular and renal-based; this makes GLP-1 RAs a great option as they have shown to improve these outcomes in this patient population. Efpeglenatide is an exendin-4 (animal) based GLP-1 RA with a long half-life, thus administered subcutaneously once weekly. The purpose of the study is to assess the effectiveness of efpeglenatide in patients with type 2 diabetes concerning cardiovascular and kidney outcomes. 

The AMPLITUDE-O trial was an international, randomized clinical trial with 4076 patients with type 2 diabetes grouped into three intervention arms, 4 mg or 6 mg treatment (n= 2715), or placebo (n= 1358). The baseline characteristics of the sampled population were majority white males with an average of 64.5 ±8.2 years with a diabetes duration of 15.4 ±8.8 years and 90% having prior cardiovascular disease, 32% with an eGFR <60 mL/min/1.73m2, and an average HbA1c of 8.9%. The first primary endpoint is if efpeglenatide is non-inferior to placebo regarding MACE outcomes (non-fatal MI and stroke, or death from cardiovascular or undetermined causes). The other primary endpoint was the renal composite outcomes (new macroalbuminuria, decreased eGFR by >40%, kidney replacement therapy, and eGFR <15 mL/min/1.73m2) in patients with type 2 diabetes. If non-inferiority was proven, then secondary endpoints were evaluated, such as efpeglenatide superiority to placebo with regards to MACE, MACE/ coronary revascularization/ unstable angina hospitalization, and new or worsening nephropathy. 

The clinical effects of efpeglenatide on HbA1c showed a reduction from 8.9% to 7.5% by 24 months, with a -1.24% [95% Confidence Interval (CI): 1.17 to 1.32, P-Value <0.001] treatment difference in HbA1c when compared to the placebo group. The placebo group had more glucose-lowering agents, especially SGLT-2i, than the treatment group but only reached an HbA1c of 8.4%. Adverse events such as severely low blood glucose (0.9%, P-Value= 0.67), retinopathy (1.7%, P-Value= 0.5), and pancreatic events (1.2%, P-Value= 0.87) were minimal in the treatment group and did not pose a greater risk.  

Efpeglenatide demonstrated a hazard ratio of 0.73 (95% CI: 0.58 to 0.92), P-Value (non-inferiority at 1.3 margin) <0.0001, and a P-Value (superiority)= 0.0069 for the MACE outcomes. With a hazard ratio of 0.79 (95% CI: 0.65 to 0.96, P-Value= 0.020), MACE/ coronary revascularization/ unstable angina hospitalization outcomes were superior in efpeglenatide than placebo. Efpeglenatide again displayed superiority in nephropathy outcomes with a hazard ratio of 0.68 (95% CI: 0.57 to 0.79, P-Value <0.0001) compared to placebo. An exploratory analysis concluded that MACE outcomes with and without SGLT-2i use had an interaction P-Value of 0.68. Thus, both groups have the same overall hazard ratio of 0.73 (95% CI: 0.58 to 0.92). Moving onto the kidney outcomes of efpeglenatide, a 21% lower (95% CI: 14 to 28, P-Value <0.001) urine albumin: creatinine ratio (UACR) occurred in the treatment group compared to placebo. The treatment group also experienced an eGFR that was 0.87 mL/min/1.73m2 higher (95% CI: 0.27 to 1.51, P-Value= 0.005) compared to placebo. Overall, the kidney composite outcome had a hazard ratio of 0.68 (95% CI: 0.57 to 0.79, P-Value <0.0001) compared to the placebo group.  

Use of Glucose-Lowering Agents at Final Visit 

• Efpeglenatide 
  • Metformin (%): 1975 (72.7) 
  • Sulfonylureas (%): 652 (24) 
  • Insulin (%): 1723 (63.5) 
  • SGLT-2i (%): 475 (17.5) 

• Placebo 
  • Metformin (%): 991 (73) 
  • Sulfonylureas (%): 354 (26.1) 
  • Insulin (%): 884 (65.1) 
  • SGLT-2i (%): 288 (21.2) 

 To summarize, efpeglenatide use in patients with type 2 diabetes with significant risks for cardiovascular and renal complications was effective and safe. It had demonstrated that not only was it non-inferior to placebo, but it proved to be superior to the placebo group for the MACE outcomes. In addition, the efpeglenatide also had better HbA1c reduction. Cardiovascular outcomes favored the treatment group and the renal composite outcome, mainly due to efpeglenatide significantly decreasing albuminuria and the rate of decline in eGFR. Therefore, efpeglenatide will provide a favorable choice to providers when determining a GLP-1 RA for a patient with type 2 diabetes that needs cardiovascular and renal protective benefits. 

Practice Pearls: 

• Efpeglenatide exhibited a safe and effective reduction in cardiovascular and renal outcomes. 
• Efpeglenatide had a favorable reduction in HbA1c compared to placebo. 
• There was no difference in effect when comparing the combination of efpeglenatide and an SGLT-2i vs. efpeglenatide alone for MACE outcomes. 

Gerstein, Hertzel C et al. “Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.” American Diabetes Association 81st Scientific Sessions. Diabetes, June 28, 2021 (Requires ADA Symposium login.) 

Alan Martinez, PharmD Candidate, University of South Florida Taneja College of Pharmacy