Cystatin C- and Creatinine-Based Estimates of Glomerular Filtration Rate in Dapagliflozin Phase 3 Clinical Trials

Abstract

Introduction: To compare estimated glomerular filtration rate measured by serum creatinine (eGFRcr) and serum cystatin C (eGFRcys) in patients with type 2 diabetes mellitus from dapagliflozin clinical trials.

Methods: Post hoc analysis of data pooled from 9 phase 3, randomized, placebo-controlled, 24-week trials of dapagliflozin. The correlation between eGFRcr and eGFRcys was modeled by a simple linear regression. The proportions of patients with eGFR 30 to <60 and ≥60 mL/min/1.73 m(2) based on creatinine versus cystatin C were compared.

Results: Of 4745 total patients, 4294 (90.5%) had serum cystatin C data available for calculation of eGFRcys. The correlation between eGFRcr and eGFRcys was poor (R (2) = 30%). Of patients with eGFRcr 30 to <60 mL/min/1.73 m(2), 66% had eGFR ≥60 when recalculated based on cystatin C. Among patients with eGFRcr ≥60 mL/min/1.73 m(2), 95.8% had eGFR ≥60 when estimated using cystatin C. Decreases in HbA1c, body weight, and systolic blood pressure with dapagliflozin were similar among patient subgroups defined by either eGFR estimate and were statistically significant and clinically meaningful with dapagliflozin 10 mg/day in most subgroups.

Conclusion: The correlation between eGFRcr and eGFRcys was poor. Renal function assessed by eGFRcr may be underestimated, and some patients may be misdiagnosed with chronic kidney disease and/or unjustifiably deemed ineligible for certain antidiabetes medications. This is in consonance with guidelines suggesting using eGFRcys as a confirmatory measure when eGFRcr is between 45 and <60 mL/min/1.73 m(2) with no evidence of kidney damage and/or in other situations where eGFRcr may be unreliable.

Funding: AstraZeneca.

Keywords: Chronic kidney disease; Dapagliflozin; GFR; Glomerular filtration; Serum creatinine; Serum cystatin C; Sodium-glucose cotransporter; Type 2 diabetes.

Fig. 1

Correlation of baseline eGFRcr vs eGFRcys. DAPA dapagliflozin, eGFR estimated glomerular filtration rate, eGFRcr creatinine-based eGFR, eGFRcys cystatin C-based eGFR, PBO placebo, R ² coefficient of determination

Fig. 2

Adjusted mean change from baseline in HbA_1c (a), body weight (b), and seated SBP (c) stratified by creatinine-based and cystatin C-based eGFR. CI confidence interval, DAPA dapagliflozin, eGFR estimated glomerular filtration rate, eGFRcr creatinine-based eGFR, eGFRcys cystatin C-based eGFR, PBO placebo, SBP systolic blood pressure. *P < 0.0001, ^† P = 0.015, ^‡Data not shown, n = 8–9, ^§ P = 0.021, ^¶ P = 0.013, ^# P = 0.0002 versus placebo