Nephrotic-range proteinuria in type 2 diabetes: Effects of empagliflozin on kidney disease progression and clinical outcomes

Abstract

Background: Diabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressive kidney disease, in a post-hoc analysis of data from the EMPA-REG OUTCOME trial (NCT01131676).

Methods: Cox proportional hazards models were used to investigate the risk of cardiovascular and kidney outcomes in participants with and without NRP, defined by urine albumin-to-creatinine ratio (UACR) ≥2200 mg/g at baseline. Annual loss of eGFR during chronic treatment (eGFR slopes) and hypothetical time to projected end-stage kidney disease (ESKD), conditioning upon linearity of eGFR change over time if a patient did not decease before projected ESKD, were calculated using a random-intercept random-coefficient model. Safety was described based on investigator-reported adverse events.

Findings: 112 participants (pooled empagliflozin, n = 70; placebo, n = 42; median on-treatment follow-up of 1·9 years on placebo compared with 2·3 years on empagliflozin) presented with NRP at baseline; eGFR and UACR were balanced between treatments. Empagliflozin benefits on cardiovascular death, hospitalisation for heart failure, or kidney outcomes, were consistent in participants with and without NRP (pinteraction >0·1). Treatment effects of empagliflozin on adjusted annual mean eGFR slope were more pronounced in participants with NRP versus those without (pinteraction 0·005). Empagliflozin was estimated to double the median hypothetical time to projected ESKD in participants with NRP. The overall safety profile of empagliflozin was comparable between participants with and without NRP at baseline.

Interpretation: Our data suggests that empagliflozin might slow kidney function loss and delay the estimated onset of projected ESKD in patients with type 2 diabetes and cardiovascular disease complicated by NRP.

Keywords: Empagliflozin; Kidney disease; Nephrotic; Proteinuria; SGLT2 inhibitor; Type 2 diabetes.

Conflict of interest statement

PR and GR have no conflicts to report. BJK is an employee of Boehringer Ingelheim, the University Hospital of Würzburg and has received grants from the IZKF (Interdisziplinaeres Zentrum fuer klinische Forschung) of the University of Wuerzburg, and from Boehringer Ingelheim. SI reports consulting fees and honoraria from Intarcia Therapeutics, Daiichi-Sankyo, Lexicon Pharmaceuticals, Janssen, Sanofi, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. BZ has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi Aventis. SH, MM, MvE, and AKW are employees of Boehringer Ingelheim. CW reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Mitsubishi, and MSD.

© 2021 Published by Elsevier Ltd.

Figures

Figure 1

Cardiovascular and kidney outcomes by participants with NRP (UACR ≥2200 mg/g) and non-NRP (UACR 2 or initiation of KRT or death from kidney disease.

Figure 2

Change in eGFR per week/year during prespecified study periods Participants treated with at least one dose of study drug. Adjusted mean slopes represent the average change in eGFR (MDRD) per mL/min/1.73 m2 per week (for initiation and cessation) and per year (for chronic maintenance treatment) for prespecified study periods based on random intercept random coefficient model. p-value for interaction of subgroup (NRP/non-NRP) by treatment by time, All EMPA and placebo. BL=baseline. CI=confidence interval. eGFR=estimated glomerular filtration rate. EMPA=empagliflozin. LVOT=last value on treatment. MDRD=Modification of Diet in Renal Disease. NRP=nephrotic-range proteinuria. UACR=urine albumin-to-creatinine ratio. Wk=week.

Figure 3

Time to first sustained eGFR decline ≥40% and sustained reduction in UACR of ≥30% in participants with NRP (UACR ≥2200 mg/g) Kaplan Meier estimates. HR (95% CI) based on Cox Regression. Participants treated with at least one dose of study drug. Estimates for the sustained eGFR decline ≥40% and sustained reduction in UACR of ≥30% in the non-NRP (not shown) were HR 0.56 (0.40, 0.79) and 1.25 (1.16, 1.35), respectively. CI=confidence interval. eGFR=estimated glomerular filtration rate. HR=hazard ratio. MDRD=Modification of Diet in Renal Disease. UACR=urine albumin-to-creatinine ratio.

Figure 4

Distribution of hypothetical time (years) to projected ESKD for individual patients, NRP group Median hypothetical time to projected ESKD: 5.0 [IQR 3.0, 6.9] years in placebo, 10.1 [IQR 7.4, 13.7] years in empagliflozin (p < 0•0001) Bars represent the percentage of patients in each treatment group that are estimated to reach hypothetical time (years) to projected ESKD, if a patient does not die before projected ESKD. Hypothetical ESKD per year after initiation of randomised treatment (i.e., at 5 years, 22•6% of NRP patients on placebo versus 3•4% patients on empagliflozin treatment were estimated to reach hypothetical ESKD). Patients treated with at least one dose of study drug. Hypothetical time to projected ESKD defined as time to eGFR (MDRD) reaching ≤ 10 mL/min/1•73 m2 based on estimated eGFR using the random intercept random coefficient model applied to observations from week 4 to last week on treatment (conditioning upon linearity). At maximum of 15 years all patients are considered to projectably have reached hypothetical ESKD. eGFR=estimated glomerular filtration rate. ESKD=end-stage kidney disease. NRP=nephrotic range proteinuria.

Figure 5

Adverse event profile in NRP patients Analysis based on participants treated with at least one dose of study drug. There were no episodes of venous embolic/thrombotic adverse events or diabetic ketoacidosis. NRP=nephrotic-range proteinuria.