Long-term benefits of dapagliflozin on renal outcomes of type 2 diabetes under routine care: a comparative effectiveness study on propensity score matched cohorts at low renal risk

Abstract

Background: Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D.

Methods: We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function.

Findings: We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR <60 ml/min/1.73 m² and 15% had UACR >30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m² (95% C.I. from 1.13 to 2.48; p < 0.0001). The mean eGFR slope was significantly less negative in the dapagliflozin group by 0.67 ml/min/1.73 m²/year (95% C.I. from 0.47 to 0.88; p < 0.0001). Albuminuria declined significantly in new-users of dapagliflozin within 6 months and remained on average 44.3 mg/g lower (95% C.I. from -66.9 to -21.7; p < 0.0001) than in new-users of comparators. New-users of dapagliflozin had significantly lower rates of new-onset CKD, loss of kidney function, and a composite renal outcome. Results were confirmed for all SGLT2 inhibitors, in patients without baseline CKD, and when GLP-1RA were excluded from comparators.

Interpretation: Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk.

Funding: Funded by the Italian Diabetes Society and partly supported by a grant from AstraZeneca.

Keywords: Chronic kidney disease; Observational; Prevention; SGLT2 inhibitors; Type 2 diabetes.

Fig. 1

Studyflowchart.

Fig. 2

Change in eGFR and albuminuria in the primary ITT analysis. a) Change in eGFR over time in the two groups (primary outcome). The table at the bottom of the panel shows the number of patients contributing with data at each time point. This is the primary analysis performed, on average on a total of 6197 patients/group contributing with eGFR values, though not all patients had available baseline eGFR. Baseline eGFR was imputed only for PSM, but imputed data were not used for outcome evaluation. b) Total and chronic (6 months on) eGFR slopes in the two groups (bars indicate 95% C.I.). c) Adjusted change in albuminuria (urinary albumin excretion rate, UACR) over time in the two groups and in the split of the population by baseline normo- (d) or micro-macroalbuminuria (e). The table at the bottom of the panel shows the number of patients contributing with data at each time point. The observation period was cut at 54 months.

Fig. 3

Summary of results. The forest plot show, for the intention-to-treat (ITT, a) and the on-treatment (OT, b) populations, the crude rates/1000 patient year events (PYE), the hazard ratio (HR) with 95% confidence intervals (C.I.) and the respective p-values for each categorical outcome.

Fig. 4

Kaplan–Meier curves for selected outcomes. Data from Cox proportional hazard models were used and the cumulative proportion of patients with an event is shown. Hazard ratios (HR) with 95% confidence intervals (C.I.) are presented. Number of patients at risk at each time points are also displayed.

Fig. 5

Effects on intermediate endpoints. The panels show the change over time in HbA1c (a), body weight (b), systolic blood pressure (SBP, c) and diastolic blood pressure (DBP, d) in the dapagliflozin and comparator groups. Mean differences between groups are reported on the top part. The table at the bottom of each panel shows the number of patients contributing with data at each time point. Note that the observation period was cut at 54 months.

Fig. 6

Subgroup analysis. For the primary endpoint (change in eGFR), the analysis was repeated in subgroups of patients based on key clinical characteristics at baseline. The mean change in eGFR is reported for each strata and the p-values for interaction are also displayed.