SGLT2 inhibitor ertugliflozin fails to prevent HF hospitalization at EF>60 percent: VERTIS CV analyses

Sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce the risk of HHF among those with heart failure (HF) with reduced ejection fraction. However, not much is known about the treatment efficacy at or above the normal EF range (>60%).

VERTIS CV was the cardiovascular (CV) outcome trial for ertugliflozin in type 2 diabetes mellitus (T2DM) patients and atherosclerotic cardiovascular (CV) disease. In the trial, ertugliflozin met the non-inferiority criterion for the primary endpoint of major adverse CV events. However, it did not meet superiority for the secondary endpoints, including HHF or CV death, CV death (alone), and a kidney composite (renal death, dialysis/transplantation, doubling of serum creatine). Pre-specified secondary analyses showed a significant 30% risk reduction in first and total HHF. 24% of participants had a history of HF in the VERTIS CV trial.

In the post hoc analysis, Ambarish Pandey, University of Texas Southwestern Medical Center, Dallas, TX, USA, and colleagues evaluated the effects of ertugliflozin on the risk of first and total HHF across the spectrum of pre-trial EF.

The VERTIS CV trial included 8246 participants aged ≥40 years. They were randomized in a ratio of 1:1:1 to receive once-daily ertugliflozin (5 mg, 15 mg), or placebo with a mean follow-up of 3.5 years.

Data on pre-trial EF were obtained from medical records with the EF closest to the randomization date recorded. Treatment effects of ertugliflozin versus placebo on the risk of first and total heart failure hospitalization were analyzed using adjusted Cox models for first HHF and Andersen–Gill models for total (i.e. first + recurrent) HHF events.

The researchers reported the following findings:

· In the overall cohort, ertugliflozin (vs. placebo) significantly reduced the risk of the first HHF [hazard ratio (HR) 0.70].

· In the subgroup analysis by pre-trial EF, the interaction between treatment and EF did not reach significance for the first HHF. However, the strength of association between ertugliflozin and the risk of first HHF is numerically greater among participants with EF ≤ 45% (HR 0.48) than in other groups.

· The treatment effect of ertugliflozin for the first HHF among participants with EF > 60% (HR 0.72) was comparable with that observed in the overall cohort.

· Ertugliflozin reduced the risk of total HHF events [rate ratio (RR) 0.70] in the overall cohort.

· The treatment effect of ertugliflozin on total HHF appeared to be modified by pre-trial EF, with the greatest benefit noted among those with ≤45% (RR 0.39).

· The treatment effect of ertugliflozin on total HHF was attenuated among participants with EF > 60% (RR 0.68).

· Similar findings were observed in restricted quadratic splines across a continuous EF such that ertugliflozin reduced the risk of first HHF consistently across the EF distribution but had a greater treatment effect for reducing total HHF among individuals with lower (vs. higher) pre-trial EF.

"Taken together, our study findings suggest that the ertugliflozin's treatment effect on HHF demonstrated in the overall analyses is exaggerated at lower pre-trial EF thresholds (<45%) and attenuated at higher EF thresholds," the researchers concluded.

Reference:

Pandey, A., Kolkailah, A. A., Cosentino, F., Cannon, C. P., Frederich, R. C., Cherney, D. Z., Pratley, R. E., Cater, N. B., Gantz, I., Mancuso, J. P., & McGuire, D. K. Ertugliflozin and hospitalization for heart failure across the spectrum of pre-trial ejection fraction: Post-hoc analyses of the VERTIS CV trial. European Heart Journal. https://doi.org/10.1093/eurheartj/ehad639