Initial eGFR Changes with Ertugliflozin and Associations with Clinical Parameters: Analyses from the VERTIS CV Trial

Abstract

Introduction: Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) "dip" with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated.

Methods: Patients were categorized into tertiles based on change in eGFR at week 6: >+1.00 mL/min/1.73 m2 (tertile 1), >-5.99 and ≤+1.00 (tertile 2), and ≤-6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline-week 6) and chronic periods (week 6-30 days after last dose of trial medication).

Results: In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m2/year; weeks 6-156) were -0.76 (-1.03, -0.50), -0.29 (-0.51, -0.07), and -0.05 (-0.26, 0.17) in tertiles 1, 2, and 3, respectively (p value <0.001), and approximately -1.5 mL/min/1.73 m2/year across tertiles in the placebo group (p value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were -0.77, -0.71, and -0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All pinteraction values were <0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups.

Conclusion: With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.

Keywords: Clinical trial; Diabetic nephropathy; Glomerular filtration rate; Kidney function decline; Kidney protection; Sodium-glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus.

Fig. 1

LSM change from baseline in eGFR over time by tertile of 6-week change in eGFR (a) and chronic yearly eGFR slope from week 6 to 156 by tertile of 6-week change in eGFR (b). Chronic yearly eGFR slope from week 18 to 156 by tertile of 6-week change in eGFR (c). CI, confidence interval; eGFR, estimated glomerular filtration rate; LSM, least squares mean.

Fig. 2

LSM change from baseline in glucosuria-related measures by tertile of 6-week eGFR change in the pooled ertugliflozin group: HbA1c (a), body weight (b), and serum uric acid (c). BL, baseline; CI, confidence interval; HbA1c, glycated hemoglobin; LSM, least squares mean.*95% CIs between tertiles 1 and 3 do not overlap. P_Interaction < 0.001 for all measures.

Fig. 3

LSM percent change from baseline in UACR by tertile of 6-week change in eGFR in the pooled ertugliflozin group in all patients (a), patients with normoalbuminuria at baseline (b), patients with elevated albuminuria at baseline and LSM change from baseline in natriuresis-related measures by tertile of 6-week eGFR change from baseline in the pooled ertugliflozin group (c): hematocrit (d), hemoglobin (e), SBP (f), and DBP (g). BL, baseline; CI, confidence interval; DBP, diastolic blood pressure; LSM, least squares mean; SBP, systolic blood pressure; UACR, urinary albumin-to-creatinine ratio. *95% CIs between tertiles 1 and 3 do not overlap.