Renal Mechanism of SGLT2 Inhibition

Inclusion Criteria:

• Aged 18-80 years. The lower age limit was set so renal function test results wouldnot reflect changes associated with growth.

• Diagnosis of type 2 diabetes for ≥ 3 years.

• Estimated GFR >45 and < 90 ml/min/1.73m2 as determined from the CKD-EPI equationusing serum creatinine (Levey et al., 2009).

• A screening urinary albumin-to-creatinine ratio <3000 mg/g.

• Willingness to participate after receiving a thorough explanation of the study.

• Participants receiving a RAAS inhibitor must have been receiving the drug at maximumtolerable dose for at least 3 months prior to the study baseline examination.

• Participants receiving a GLP-1 receptor agonist must have been receiving the drugfor at least 3 months prior to the study baseline examination.

Exclusion Criteria:

• Clinically significant disorders of the liver [cirrhosis, portal hypertension,hepatitis, increased bilirubin (≥1.5 mg/dl), active or uncontrolled cardiovasculardisease, symptomatic peripheral vascular disease, (i.e. intermittent claudication),pulmonary diseases (including uncontrolled asthma and restrictive or obstructivelung disease requiring therapy), renal-urinary disorders (calculi, urinary tractobstruction, glomerulonephritis, chronic infection), gastrointestinal disorders (nausea, vomiting, diarrhea or anorexia sufficient to cause weight loss or wasting),or hematocrit levels ≤30 percent in women or ≤35 percent in men.

• Prior treatment with SGLT2 inhibitors and unable to perform a wash-out.

• Renovascular or malignant hypertension; uncontrolled hypertension (systolic bloodpressure ≥150 or diastolic ≥90 mm Hg)

• Hematuria of unknown etiology. Prior to entry into the study, any participant withhematuria should be evaluated, the etiology established and documented, andtreatment rendered as appropriate.

• Chronic debilitating disorders with or without treatment (e.g., systemic lupuserythematosus [SLE], cancer, amyloidosis, and chronic infection) that wouldinterfere with the assessment of kidney function or that might reduce the chances ofsurvival for a sufficient length of time to evaluate the efficacy of treatment.

• Currently receiving a drug regimen that includes steroids, immunosuppressants, orinvestigational new drugs not associated with this trial.

• Pregnancy. SGLT2 inhibitors are not recommended during the second or third trimesterof pregnancy. Moreover, we do not wish to expose pregnant women to conscioussedation that is used during the kidney biopsies or to the intravenous filtrationmarkers iohexol and p-aminohippurate needed for the renal clearance studies. Womenof childbearing potential must have a negative pregnancy test prior to entry andevery 2 months during the study and agree to using an effective form ofcontraception throughout the study, such as the oral contraceptive pill or anintrauterine device. Women who are planning a pregnancy in the next three years willbe excluded.

• Known hypersensitivity to canagliflozin or iodine.

• Bleeding disorders or requirements for anticoagulation or platelet inhibitors whichcannot be safely interrupted, since kidney biopsies cannot be performed safely inthese individuals.

• Massive obesity with body mass index ≥45 kg/m². Kidney biopsies are more technicallydifficult with massive obesity.

• Allergy to iodine-containing contrast material or shellfish.

• Non-diabetic kidney disease - based on clinical history or kidney biopsyexamination.

• History of osteoporotic fracture.

• Conditions likely to interfere with informed consent or compliance with theprotocol.

• Single kidney; any condition with a single kidney

• Kidney cortex <1 cm (both kidneys)

• Kidney length <8 cm (both kidneys)