TABLE 2.

The DARWIN‐Renal protocol synopsis

Study title	Comparative effectiveness of dapagliflozin vs non‐insulin, non‐SGLT2i glucose‐lowering medications on renal‐wide endpoints in type 2 diabetes. A real‐world Italian multicenter study. DApagliflozin Real‐World evIdeNce (DARWIN) ‐ Renal
Sponsor	Italian Diabetes Society
Study rationale	See text
Study objectives	Primary To compare kidney function over time in patients who initiated dapagliflozin as compared to patients who initiated other non‐insulin GLMs (all except SGLT2 inhibitors) in the same period. For the primary endpoint, kidney function will be evaluated as eGFR, calculated by creatinine equation developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI). eGFR slope will be calculated Secondary To compare variations in the overall renal burden during therapy with dapagliflozin vs. other GLMs, defined as follows: Change over time in systolic and diastolic blood pressure; Change over time in HbA1c (for mediation analysis, see below); Change over time in body weight (for mediation analysis, see below); Change in the type and dosage of concomitant diuretics and blood pressure‐lowering medications (prespecified categories are: calcium channel blockers, beta‐blockers, drugs acting on the renin‐angiotensin system, alpha‐blockers); New‐onset CKD, defined as two consecutive eGFR values <60 mL/min/1.73 m2 > 90 days apart, during the entire observation; Deterioration of CKD stage (from categories: ≥90, 60‐90, 45‐60 or 30‐45 ml/min/1.73 m2) at the last observation; ≥30% or ≥ 40% reduction in eGFR at the last observation 61 ; Doubling of serum creatinine (ie, reduction of >57% in eGFR) at any time point during observation; ESKD (defined as confirmed eGFR <15 mL/min/1.73 m2) or need for RRT at any time point during observation; Change in albumin excretion rate over time; Moving category of AER. The following categories will be considered (in mg/g creatinine): normoalbuminuric [0‐10 mg/g] high‐normal albuminuric [11–29 mg/g] microalbuminuric [30‐299 mg/g] macroalbuminuric [300+ mg/g]. We will look at any progression and any regression at the end of observation compared to baseline. We will also investigate progression from normo‐ to micro‐/macroalbuminuria and from normo‐/micro‐ to macroalbuminuria. Change in uric acid concentrations.
Study design	Retrospective, observational, multicentre
Setting	Diabetes specialist outpatients clinics in Italy
Population	People with type 2 diabetes
Enrolment criteria	Inclusion criteria i) Age 18‐80 years; ii) Diagnosis of T2D; iii) Disease duration 1 year or more, as established since the date of T2D diagnosis in the chart; iv) Initiation of dapagliflozin or comparators; between 2015 and 2020 v) Availability of pre‐ and post‐index date information on renal outcomes (see below for the minimum set of endpoint data). Exclusion criteria i) Other forms of diabetes (eg, type 1 diabetes or gestational diabetes); ii) age < 18 or > 80 years; iii) previous therapy with another SGLT2 inhibitors in the 12 months before the index date; iv) CKD stage V (eGFR <15 mL/min/1.73 m2) or ongoing dialysis at baseline
Number of patients	1130 / group post‐matching (based on a eGFR slope difference > 0.8 mL/min/1.73 m2/year)
Number of centres	50
Study duration	Enrolment between 2015 and 2020. Follow‐up until last observation. Expected mean observation 2.5‐3.0 years.
Expected timeline	EC approval (actual): Oct 2020 Centre enrolment (ongoing): Nov 2020 to Nov 2021 Database lock (estimated): Dec 2021 Primary completion (estimated): Jun 2022
Statistical analysis plan	Descriptive statistics will be used to report baseline clinical characteristics Matching will be performed by PSM with 1:1 or 1:2 or 1:3 ratio according to the final numbers of unmatched patients in the two groups. Good balance between groups will be defined when absolute standardized mean difference are <10%. Matching variables will include the pre‐index date eGFR slope. The primary outcome will be analysed using the mixed model for repeated measures. eGFR slope will be calculated with or without the acute phase. For categorical endpoints, the proportion of patients in the two groups will be compared by chi‐squared test or logistic regression models. Missing data will be handled by multiple imputation. Subgroup analyses will be performed by age, sex, diabetes duration, HbA1c, baseline eGFR category and KDIGO categories of CKD, 62 history of other microangiopathies (including albuminuria categories), cardiovascular disease, concomitant therapies.

Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GLM, glucose‐lowering medication; HbA1c, glycated haemoglobin.