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Long-Awaited Cardiovascular Efficacy and Safety Results From VERTIS-CV

Aug 18, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Lawand Kamal, PharmD Candidate 2021, Skaggs School of Pharmacy and Pharmaceutical Sciences

Results from the VERTIS-CV trial suggest that ertugliflozin is not superior to placebo in reducing MACE but may reduce the rate of hospitalization for heart failure. 

The “Design and Baseline Characteristics of the eValuation of ERTugliflozin effIcacy and Safety Cardiovascular Outcomes Trial (VERTIS-CV)” was published in late 2018 to introduce a study looking at cardiovascular (CV), renal safety, and the efficacy of ertugliflozin in patients living with type 2 diabetes (T2D) and atherosclerotic disease (ASCVD). Ertugliflozin is a relatively new sodium-glucose cotransporter type 2 (SGLT2) inhibitor that was FDA approved in late 2017 for patients living with T2D. Drugs in the same class, such as canagliflozin, have demonstrated beneficial CV (CANVAS) and renoprotective (CREDENCE) outcomes. However, not all SGLT2 inhibitors have similar class effects. For example, dapagliflozin was recently able to show significant benefits in patients with heart failure and a reduced ejection fraction in the DAPA-HF trial, leading to another new indication for this drug. Diving into the VERTIS-CV trial results will help further distinguish ertugliflozin and the role this medication has among the other SGLT2 inhibitors currently on the market. 


A randomized, multicenter, double-blind, placebo-controlled, event-driven trial by Cannon et al. was designed to demonstrate non-inferiority of ertugliflozin vs. placebo on major adverse CV events (MACE), which includes: time to the first event of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke. Multiple secondary objectives were created to demonstrate the superiority of ertugliflozin vs. placebo in various CV and renal composite endpoints. The trial included 8246 patients with T2D and ASCVD from across 34 countries where patients were randomized (1:1:1) to receive either ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo, once daily. The average duration of follow-up in the study overall was 3.5 years, where primary and secondary outcomes were analyzed by the Cox proportional hazards model. 

The primary composite outcome (MACE) was observed in 11.9% of patients taking ertugliflozin and in 11.9% of patients taking a placebo with an HR 0.97 (95.6% CI, 0.85, 1.11) where p<0.001 for non-inferiority. No statistically significant difference for superiority between ertugliflozin and placebo for the individual MACE components (CV death, nonfatal MI, nonfatal stroke) was observed. 

In regards to secondary endpoints, the study (percentage of patients) failed to show superiority for ertugliflozin (8.1%) vs. placebo (9.1%) for the composite of CV death and hospitalization for heart failure (HHF) with an HR 0.88 (95.8% CI, 0.75, 1.03) where p=0.11 for superiority. Results regarding CV death alone were nonsignificant with an HR 0.92 (95.8% CI, 0.77, 1.11) where p=0.39 for superiority. However, HHF examined by itself (prespecified endpoint), produced results in favor of ertugliflozin (2.5%) vs. placebo (3.6%) with an HR 0.70 (95% CI, 0.54, 0.90) where p=0.006 for superiority. No statistically significant difference in the renal composite (renal death, dialysis/transplant, or doubling of serum creatinine) outcome was observed with an HR 0.81 (95.8% CI, 0.63, 1.04) where p=0.08 for superiority. Differences in safety outcomes between ertugliflozin vs. placebo were consistent with the results and known risks (e.g., genital mycotic infection) of other drugs in the SGLT2 inhibitor class. 

Compared to the trial results from other SGLT2 inhibitors on the market, VERTIS-CV was unable to show superiority for ertugliflozin vs. placebo outside of reductions in HHF. Perhaps the main reason for why the study was unable to show superiority for the composite of CV death and HHF was due to ertugliflozin’s inability to reduce CV death compared to placebo. Beneficial effects were similar to other SGLT2 inhibitors in terms of the combined renal outcome, which trended towards superiority for ertugliflozin despite the results not being statistically significant. The authors inferred that there might be inherent differences in the mechanism of action and off-target effects between SGLT2 inhibitors, leading to various MACE and CV death results across this class of medication. While the VERTIS-CV trial results appear to be lackluster compared to other SGLT2 inhibitors on the market, ertugliflozin’s safety and efficacy profiles were demonstrated by achieving the primary endpoint of non-inferiority for MACE and by showing HHF benefits. 

Practice Pearls: 

  • Ertugliflozin achieved the primary endpoint of non-inferiority for MACE compared to placebo in patients living with T2D and ASCVD but failed to show superiority. 
  • Secondary endpoints, including the composite of CV death/HHF and renal composite outcomes, did not show statistical significance for ertugliflozin compared to placebo. 
  • Similar to other SGLT2 inhibitors, ertugliflozin shows statistically significant reductions in HHF, which further supports that this benefit is likely consistent across the class. 


Cannon, Christopher P et al. “Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).” American heart journal vol. 206, (2018): 11-23. doi:10.1016/j.ahj.2018.08.016 

Neal, Bruce, et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” The New England journal of medicine vol. 377,7 (2017): 644-657. doi:10.1056/NEJMoa1611925 

Perkovic, Vlado et al. “Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.” The New England journal of medicine vol. 380,24 (2019): 2295-2306. doi:10.1056/NEJMoa1811744 

McMurray, John J V et al. “Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.” The New England journal of medicine vol. 381,21 (2019): 1995-2008. doi:10.1056/NEJMoa1911303 

Cannon, Christopher P, et al. “Results of the eValuation of ERTugliflozin EffIcacy and Safety Cardiovascular Outcomes Trial (VERTIS CV).” Presented at: 80th American Diabetes Association Scientific Sessions; June 16, 2020. Symposium. 

Lawand Kamal, PharmD Candidate 2021, Skaggs School of Pharmacy and Pharmaceutical Sciences  


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