Ertugliflozin CV Outcomes in T2D Population Are Similar to Placebo

September 23, 2020

In patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease, results from a multicenter, double-blind trial show that treatment with ertugliflozin is noninferior to placebo with respect to major adverse cardiovascular events.

In patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease, results from a multicenter, double-blind trial show that treatment with ertugliflozin is noninferior to placebo with respect to major adverse cardiovascular events (MACE). Results of the study were published in the New England Journal of Medicine.

Ertugliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor originally approved by the FDA for the improvement of glycemic control in adults with T2D. Recent studies have demonstrated that the class as a whole is effective in treating certain forms of heart failure (HF).

In patients with T2D, cardiovascular disease is the leading cause of illness and death, while T2D is also a major risk factor for developing HF and progression of renal disease. However, the specific cardiovascular (CV) effects of ertugliflozin in this population have not been established.

While continuing standard care, eligible patients were randomly assigned 1:1:1 to receive 5 mg or 15 mg of ertugliflozin or matching placebo once daily for 18 weeks. Primary outcomes included a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke (all were considered MACE). Secondary outcomes consisted of a composite of death from CV causes or hospitalization for HF, death from CV causes, and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level.

Between December 2013 and July 2015 and from June 2016 through April 2017, a total of 8246 participants were enrolled in 2 cohorts (cohort 1, n = 4023; cohort 2, n = 4223). Patients were followed for a mean of 3.5 years, and a total of 8238 patients received at least 1 dose of ertugliflozin or placebo.

Analyses revealed:

  • A MACE occurred in 653 of 5493 patients (11.9%) in the ertugliflozin arm and in 327 of 2745 patients (11.9%) in the placebo arm (HR, 0.97; 95.6% CI, 0.85-1.11; P < .001 for noninferiority).
  • Death from CV causes or hospitalization for HF occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (HR, 0.88; 95.8% CI, 0.75-1.03; P = .11 for superiority).
  • HR (ertugliflozin vs placebo) for death from CV causes was 0.92 (95.8% CI, 0.77-1.11).
  • HR for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63-1.04).
  • Amputations were performed in 54 patients who received a 5-mg dose of ertugliflozin (2%), 57 patients who received a 15-mg dose (2.1%), and 45 patients who received placebo (1.6%).
  • At week 18, least-squares mean difference from baseline in glycated hemoglobin (A1C) level was –0.7% (95% CI, –0.7% to –0.69%) among those who received 15 mg of ertugliflozin and –0.22% (95% CI, –0.25% to –0.19%) among those who received placebo.

“We do not have a clear explanation about why our results did not reach significance, whereas significance was reached for many (but not all) end points in previous CV outcomes trials of SGLT-2 inhibitors,” researchers wrote.

Pharmacologically similar doses of ertugliflozin were used in the present trial compared with VERTIS CV, a trial that tested the efficacy of ertugliflozin in CV outcomes. However, authors note that secular trends of more intensive preventive therapies over recent years may have had a greater impact on the current trial.

When it comes to adverse events, results from the trial are consistent with the known risks of the SGLT-2 inhibitor class. In addition to amputation, genital mycotic infections occurred more frequently among individuals in patients who received ertugliflozin compared with placebo. The percentage of patients who experienced diabetic ketoacidosis was higher in either ertugliflozin group than in the placebo group, although statistical testing was not performed.

The study was funded by Merck Sharp & Dohme and Pfizer.

Reference

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. Published online September 23, 2020. doi:10.1056/NEJMoa2004967