Literature
Clinical Pearls & Morning Reports
Published October 7, 2020
Was ertugliflozin noninferior to placebo regarding cardiovascular outcomes in the trial by Cannon et al.?
Ertugliflozin is an oral, selective sodium–glucose cotransporter 2 (SGLT2) inhibitor that was approved by the Food and Drug Administration (FDA) in the United States and by other regulatory authorities in other countries for the improvement of glycemic control in adults with type 2 diabetes. The FDA has mandated that cardiovascular safety be evaluated in trials of new glucose-lowering drugs, including SGLT2 inhibitors. Cannon et al. conducted a placebo-controlled trial (VERTIS CV) that assessed the long-term effects of ertugliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Read the NEJM Original Article here.
Clinical Pearls
Q: In the trial by Cannon et al., what was the long-term effect of ertugliflozin on renal outcomes?
A: Patients received 5 mg or 15 mg of ertugliflozin; data from the two ertugliflozin dose groups were pooled for analysis. No significant benefit of ertugliflozin was observed for the renal composite outcome (death from renal causes, renal replacement therapy, or doubling of the serum creatinine level) in this trial, whereas previous trials of other SGLT2 inhibitors have shown consistent reductions in the risk of both albuminuria and clinical renal composite outcomes.
Q: What were the hazard ratios for death from cardiovascular causes and death from any cause in the trial by Cannon et al.?
A: The hazard ratio (ertugliflozin vs. placebo) for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from any cause was 0.93 (95% CI, 0.80 to 1.08).
Morning Report Questions
Q: Was ertugliflozin noninferior to placebo regarding cardiovascular outcomes in the trial by Cannon et al.?
A: In this trial involving patients with type 2 diabetes and established atherosclerotic cardiovascular disease, ertugliflozin, when added to guideline-directed secondary prevention therapies, was shown to be noninferior to placebo with respect to major adverse cardiovascular events. A major adverse cardiovascular event (the primary outcome) occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure (the first key secondary outcome) occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P=0.11 for superiority).
Q: In VERTIS CV, what did the safety analyses show?
A: The incidence of serious adverse events and adverse events leading to permanent discontinuation of the trial regimen did not differ significantly between either ertugliflozin dose group and the placebo group. More urinary tract infections and genital mycotic infections were reported in each of the ertugliflozin dose groups than in the placebo group. The percentage of patients who underwent amputation was numerically — but not significantly — higher in either ertugliflozin dose group than in the placebo group, and the percentage of patients who had diabetic ketoacidosis was higher in either ertugliflozin dose group than in the placebo group (statistical testing was not performed). No cases of Fournier’s gangrene were reported in any group. The incidence of serious acute kidney injury, serious urinary tract infection, hypovolemia, fractures, or symptomatic or severe hypoglycemia did not differ significantly between either ertugliflozin dose group and the placebo group.