Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials

Abstract

Aims/hypothesis This study aimed to evaluate the effect of ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.gov NCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population. Methods Post hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks. Results Overall, mean (SD) baseline eGFR was 88.2 (18.8) ml min −1 (1.73 m) −2 and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were −2.3, −2.7 and −0.7 ml min −1 (1.73 m) −2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were −0.2, 0.1 and −2.0 ml min −1 (1.73 m) −2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was −29.5% (−44.8, −9.8; p < 0.01) for ertugliflozin 5 mg and −37.6% (−51.8, −19.2; p < 0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA 1c (mmol/mol [95% CI]) at week 104 were similar between treatment groups: −6.84 (−7.64, −6.03), −7.74 (−8.54, −6.94) and −6.84 (−7.65, −6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1 c (% [95% CI]) at week 104 were: −0.63 (−0.70, −0.55), −0.71 (−0.78, −0.64) and −0.63 (−0.70, −0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Conclusions/interpretation Ertugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA 1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria. Trial registration clinicaltrials.gov NCT01999218 and NCT02033889.

Nephroprotection by SGLT2 Inhibition: Back to the Future?

“…This check-mark effect suggests reduced hyperfiltration at the beginning of SGLT2i treatment that translates into the preservation of kidney structure over the long term. This peculiar hemodynamic sign heralding better kidney outcome has been a consistent finding in all the early SGLT2i trials [ 8 , 9 , 10 , 11 ], as well as in the most recent VERTIS trial in diabetic patients treated with ertuglifozin [ 44 ].…”

“…Table 1 summarizes the findings of RCTs with available results on GFR changes, comparing early (first few months) with subsequent months of treatment in experimental and placebo arms. As previously mentioned, all major trials with SGLT2i demonstrate a checkmark effect that is consistently associated with better renal outcome [ 8 , 9 , 10 , 11 , 44 ]. Figure 1 is a graphical description of the checkmark phenomenon, reporting the mean eGFR changes within the initial six months of trials and in the subsequent period of follow-up in patients administered with an experimental drug or placebo.…”

Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk

“…A 24-week Japanese study of ipragliflozin in people with T2D reported larger changes in eGFR from baseline for ipragliflozin versus placebo in patients with moderate renal impairment (eGFR 30 to < 60 mL/min/1.73 m 2 ) compared with those with mild impairment (eGFR 60 to < 90 mL/min/1.73 m 2 ; − 2 mL/min/1.73 m 2 vs − 0.5 mL/min/1.73 m 2 ) [ 63 ]. Other studies have reported no significant changes in eGFR during longer term treatment with empagliflozin [ 64 – 66 ], canagliflozin [ 67 – 69 ], dapagliflozin [ 60 , 70 , 71 ], ipragliflozin [ 72 , 73 ], ertugliflozin [ 74 ], or tofogliflozin [ 75 ]. All SGLT2 inhibitor CVOTs report an initial rapid reduction in eGFR, followed by a slower decline, or stabilization, in the SGLT2 inhibitor group compared with placebo, explaining the greater decline in eGFR after 12 weeks that was reported in some studies.…”

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

“…Regression of albuminuria (return to ACR B 3 mg/ mmol) was increased by 30% in the CANVAS study (Table 2) [28,30]. Analysis of data from the DECLARE-TIMI 58 trial revealed a reduced risk in the renal composite end point (with dapagliflozin treatment versus placebo), and the DAPA-CKD trial was halted early in March 2020 [34,37].…”

“…Analysis of data from the DECLARE-TIMI 58 trial revealed a reduced risk in the renal composite end point (with dapagliflozin treatment versus placebo), and the DAPA-CKD trial was halted early in March 2020 because of overwhelming efficacy [ 31 ]. The ertugliflozin VERTIS-CV trial demonstrated a 19% relative risk reduction with ertugliflozin for the composite renal end point, versus placebo, in people with T2DM and atherosclerotic cardiovascular disease (ASCVD) (Table 2 ) (and post hoc exploratory analysis using data from the VERTIS-SU and VERTIS-MET trials suggested that ertugliflozin provided improvements in eGFR and ACR compared with non-ertugliflozin treatment) [ 34 , 37 ].…”