Zambrowicz 2015.

Methods	Study design: parallel RCT Study time frame: 31 October 2012 to 14 August 2013 Duration of follow‐up: 7 days
Participants	Country: USA Setting: single centre Inclusion criteria: patients with type 2 DM; moderate to severe CKD (defined by an eGFR < 60 mL/min/1.73 m2) Number: treatment group (16); control group (15) Mean age ± SD (years): treatment group (64.8 ± 8.53); control group (68.1 ± 7.33) Sex (M/F): treatment group (8/8); control group (9/6) Exclusion criteria: Type 1 DM; diabetes due to a pancreatic disorder; secondary diabetes (e.g. from Acromegaly or Cushing's disease); received a kidney allograft; expecting to require dialysis or undergo kidney transplantation within 3 months of Day 1; active hepatic disease; history of MI or stable angina or coronary revascularisation within 6 months prior to start of study; clinically significant arrhythmia; congestive heart failure; uncontrolled hypertension; history of 2 or more emergency or doctor visits due to hypoglycaemia within 6 months of study or hypoglycaemia unawareness; history of alcohol or illicit drug use; any bowel condition affecting gastric emptying or malabsorptive disorder or bowel resection; history of active infection within 2 weeks of recruitment; history of major surgery within 6 months of recruitment or imminent surgery during study; history of malignancy within 5 years of recruitment; pregnant; previous reaction to SGLT2 inhibitor; previous exposure to LX4211
Interventions	Treatment group LX4211 400 mg/d Control group Placebo
Outcomes	Effect of LX4211 therapy on post‐prandial glucose levels, measured as the change from baseline to day 7 Tolerability, pharmacodynamic effects on FBG and GLP‐1 levels from baseline to day 7, and pharmacokinetics effects of single and multiple doses. including 24‐hour urine glucose excretion, BP, mean finger‐stick BGL, fractional excretion of calcium and phosphate, serum uric acid levels and fractional excretion of uric acid, fasting triglyceride levels, tumour necrosis factor α levels, leptin levels, and exogenous insulin dose Monitoring of AEs, clinical laboratory tests (chemistry, haematology, lipid profile, and urinalysis), vital signs (BP, heart rate, respiratory rate, and oral temperature), 12‐lead electrocardiograms, physical examinations, and BGL
Notes	Funding source: Lexicon Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants received LX4211 or placebo. study also described as double blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Although the study was described as double blind, the methodology behind outcome assessment blinding was not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 1 patient 1/16 (6.3%) of the LX4211 group discontinued. No patients discontinued from the placebo arm
Selective reporting (reporting bias)	Low risk	Protocol available. All major outcomes reported
Other bias	High risk	Conflicts of interest: All authors were employees of Lexicon Pharmaceuticals who funded the study and was responsible for the study design, interpretation of the data, writing of the manuscript, and the decision to submit the manuscript

ABPM ‐ ambulatory blood pressure monitoring; AE ‐ adverse event/s; AKI ‐ acute kidney injury; ALT ‐ alanine aminotransferase; ALP ‐ alkaline phosphatase; AST ‐ aspartate aminotransferase; BCC ‐ basal cell carcinoma; BGL ‐ blood glucose level/s; BMI ‐ body mass index; BP ‐ blood pressure; BUN ‐ blood urea nitrogen; CAPD ‐ continuous ambulatory peritoneal dialysis; CrCl ‐ creatinine clearance; CRP ‐ C‐reactive protein; CTR ‐ cardiothoracic ratio; CVD ‐ cardiovascular disease; DBP ‐ diastolic blood pressure; DKD ‐ diabetic kidney disease; DM ‐ diabetes mellitus; eGFR ‐ estimated glomerular filtration rate; ESA ‐ erythropoietin stimulating agent/s; ESKD ‐ end‐stage kidney disease; FBG ‐ fasting blood glucose; GI ‐ gastrointestinal; GA ‐ glycated albumin; Hb ‐ haemoglobin; HbA1c ‐ haemoglobin A1c (glycated); HD ‐ haemodialysis; HDL ‐ high‐density lipoprotein; HIV ‐ human immunodeficiency virus; HOMA‐IR ‐ homeostasis model assessment for insulin resistance; IP ‐ intraperitoneal; iPTH ‐ intact parathyroid hormone; LDH ‐ lactate dehydrogenase; LDL ‐ low‐density lipoprotein; MDRD ‐ Modification of Diet in Renal Disease; M/F ‐ male/female; MI ‐ myocardial infarction; NYHA ‐ New York Heart Association; NSAID ‐ nonsteroidal anti‐inflammatory drugs; PAH ‐ paraminohippuric acid; PD ‐ peritoneal dialysis; RBC ‐ red blood cell/s; RCT‐ randomised controlled trial; RRT ‐ renal replacement therapy; SBP ‐ systolic blood pressure; SC‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation; SEM ‐ standard error of the mean; TIA ‐ transient ischaemic attack; UACR ‐ urinary albumin/creatinine ratio; UAER ‐ urinary albumin excretion ratio; ULN ‐ upper limit of normal; UTI ‐ urinary tract infection