Does Ertugliflozin share the same cardiovascular and renal benefits recently demonstrated by other SGLT-2 Inhibitors?
Ertugliflozin is the most recent SGLT-2 inhibitor approved by the FDA. Recent studies, such as DAPA-HF and the EMPEROR-Reduced trial, have shown that SGLT-2 inhibitors have significant cardiovascular benefits in patients with and without type 2 diabetes. SGLT-2 inhibitors are now recommended to add-on to metformin in patients with type 2 diabetes and evidence of HFrEF or CKD by the American Diabetes Association. With the FDA now mandating cardiovascular safety evaluation be included in trials for new antihyperglycemic agents, VERTIS CV looked at the long-term renal and cardiovascular effects of Ertugliflozin in patients with type 2 diabetes.
This randomized, placebo-control trial aimed to show that ertugliflozin was non-inferior to placebo concerning the study‘s primary endpoint. This study’s primary endpoint was a composite of MACE, including death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The critical secondary endpoints were a composite of HF hospitalization and death by cardiovascular causes and the composite renal outcome, including renal replacement therapy, serum creatinine doubling, or death from renal causes. A test for superiority was to be conducted for the critical secondary endpoints if non-inferiority was proven in the primary endpoint. To be included in the study, patients with type 2 diabetes (A1c between 7 and 10.5%) had to be ≥ 40 years of age with atherosclerotic cardiovascular disease. Patients were excluded if they had an eGFR < 30 mL/min/1.73m2, a history of diabetic ketoacidosis, or type 1 diabetes.
Patients were randomized 1:1:1 into study arms receiving either 5 mg or 15 mg of ertugliflozin or placebo on top of the patient‘s standard diabetes therapy. Baseline characteristics were balanced in all three of the arms. The mean duration of the study was 3.0 years, with the mean follow-up period being 3.5 years.
A total of 8246 patients were enrolled in the trial, 5499 patients in the combined ertugliflozin arms, and 2747 patients in the placebo arm. MACE’s primary endpoint was reached in 11.9% of patients in the combined ertugliflozin arms and 11.9% in the placebo group (HR 0.97; 95.6% CI 0.85 – 1.11; p<0.001), demonstrating non-inferiority. In the composite secondary endpoints analysis, patients in the ertugliflozin group had a 12% lower risk of death by cardiovascular cause or hospitalization for heart failure, though not significant (HR 0.88; 95.8% CI, 0.75 – 1.03; p=0.11). A 19% lower risk of the composite renal outcomes was also seen in the combined ertugliflozin arms, though not significant (HR: 0.81, 95.8% CI 0.63-1.04). Of the remaining secondary endpoints, the risk of hospitalization for heart failure was 30% lower in the combined ertugliflozin arms though it was not tested for statistical significance (95% CI 0.54-0.90). At week 18, patients taking ertugliflozin had a lower mean reduction in A1c than patients in the placebo arm. A mean difference of -0.70% and -0.72% was seen in the 5 mg ertugliflozin and 15 mg ertugliflozin arms, respectively, and a difference of -0.22% was seen in patients who received placebo. Adverse events leading to death or permanent discontinuation of the trial regimen did not differ significantly between the groups. Rates of urinary tract infections and genital mycotic infections in both males and females were significantly higher in patients taking ertugliflozin as compared to placebo (p=0.03, p <0.001 and p <0.001, respectively)
Ertugliflozin was found to be non-inferior to placebo concerning MACE. Still, it did not show superiority to placebo in risk reduction of composite renal outcomes or the composite cardiovascular outcomes of hospitalization for heart failure or death by cardiovascular cause. Potential explanations of why ertugliflozin did not reach significance in the critical secondary outcomes include the increased intensity of secondary preventive strategies over the past few years and differences among the SGLT-2 class agents. Though the composite renal outcomes were not met, for other agents in this class, each trial had different definitions for their renal endpoints. Further analysis could be done by modifying the renal endpoints to compare the outcome to other SGLT-2 inhibitors better.
- Ertugliflozin was non-inferior to placebo in its effects on MACE, including death from cardiovascular causes, nonfatal MI, or nonfatal stroke.
- There was no difference in the critical secondary outcomes in the combined ertugliflozin and placebo arms.
- Further study can be done to better compare VERTIS CV renal outcomes to that of other SGLT-2 inhibitors.
Cannon, Christopher P. et al. “Cardiovascular Outcomes With Ertugliflozin In Type 2 Diabetes”. New England Journal Of Medicine, 2020. Massachusetts Medical Society, https://doi.org/10.1056/nejmoa2004967. Accessed October 1, 2020.
Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences