Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Abstract

Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract

Efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease using insulin: AVERTIS CVsubstudy

“…28,29 The results of this substudy have the potential to be clinically impactful in that benefits were readily and safely achieved in a population that is typically difficult to manage in clinical practice (ie, patients with long-standing T2DM and established ASCVD inadequately controlled on insulin therapy). The benefits of improved glycaemic control and reduction of BW and SBP observed with ertugliflozin, together with the potential reduction in the risk for hospitalization for heart failure 13,14 and renal outcomes 13,15 observed with ertugliflozin compared with placebo in the overall VERTIS CV study, 13 could alter disease outcome in this important population.…”

“…[7][8][9][10][11][12][13] The effects of the SGLT2 inhibitor ertugliflozin on cardiorenal outcomes in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) have been assessed in the VERTIS (eValuation of ERTugliflozin effIcacy and Safety) CV study. [13][14][15] In VERTIS CV, approximately 50% of patients were taking insulin at baseline and, in other SGLT2 inhibitor CV outcome studies, 40% to 50% of patients were on insulin at baseline. [7][8][9]13 Those percentages suggest that substantial numbers of patients with T2DM with or at high risk of ASCVD and kidney events who are using insulin in real-world clinical settings may need additional glycaemic control.…”

“…In addition to providing glycaemic control, large outcome studies have demonstrated that SGLT2 inhibitors reduce the risk of CV events, including hospitalization for heart failure, and preserve renal function 7–13 . The effects of the SGLT2 inhibitor ertugliflozin on cardiorenal outcomes in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) have been assessed in the VERTIS (e V aluation of ERT ugliflozin eff I cacy and S afety) CV study 13–15 . In VERTIS CV, approximately 50% of patients were taking insulin at baseline and, in other SGLT2 inhibitor CV outcome studies, 40% to 50% of patients were on insulin at baseline 7–9,13 .…”

Cardiorenal Protection in Diabetic Kidney Disease

“…For the key composite kidney endpoint, which used "doubling of serum creatinine" for the definition of significant kidney function loss, the impact of ertugliflozin was neutral [41]. However, as presented at the European Association for the Study of Diabetes 2020, with a more modest kidney endpoint comprised of a sustained 40% eGFR decline, a HR of 0.66 was observed (95% CI, 0.50 to 0.88) [42]. Additionally, when stratified by kidney risk in VERTIS-CV as determined by KDIGO risk categories, significant reductions in the HHF/CV death composite were observed in the moderate and high/very high risk categories (P=0.03 for interaction) [43].…”

Sodium-Glucose Co-transporter-2 Inhibitors and Nephroprotection in Diabetic Patients: More Than a Challenge

“…These data are in contrast with those obtained in other trials with SGLT2is, although the population of patients with atherosclerotic cardiovascular disease enrolled in VERTIS-CV study was broadly similar to those of previous trials performed with other SGLT2is. However, recently, has been demonstrated that when used in addition to standard of care medications, ertugliflozin is associated with a decrease in the risk of a sustained 40% decline in eGFR, with preservation of eGFR over time and a reduction of UACR in individuals with established atherosclerotic CVD and type 2 diabetes (121).…”