Mechanism of SGLT2 Inhibition in the Kidney

Inclusion Criteria:

• Aged 18-80 years.

• The lower age limit was set so renal function test results would not reflectchanges 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.

• Participants must meet the current clinical guidelines for prescribing SGLT2inhibitors, to maintain FDA-approved standards

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 and ongoing treatment with SGLT2 inhibitors

• 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 with hematuria should beevaluated, the etiology established and documented, and treatment rendered asappropriate.

• 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 trimester ofpregnancy. Moreover, we do not wish to expose pregnant women to conscioussedation that is used during the kidney biopsies.. Women of childbearingpotential must have a negative pregnancy test prior to entry and every 2 monthsduring the study and agree to using an effective form of contraceptionthroughout the study, such as the oral contraceptive pill or an intrauterinedevice. Women who are planning a pregnancy in the next three years will beexcluded.

• 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 technically difficult 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.

• History of lower-limb amputation irrespective of etiology

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

• Known solitary kidney

• Size of one or both kidneys on ultrasound < 9 cm (small kidney size is concerningfor renal atrophy due to underlying kidney disease) or > 2 cm discrepancy betweenleft and right kidney sizes based on largest longitudinal diameter

• Current use of UGT enzyme inducters, lithium, and digoxin

• Blood urea nitrogen (BUN) > 80 gm/dL

• INR > 1.4 (a)

• PTT > 35 seconds (a)

• Platelet count < 100,000 uL (a)

• Hemoglobin (Hgb) < 10 mg/dL (a)

• Hydronephrosis or other important renal ultrasound findings such as significantstone disease

1. Inclusion possible after this has been obtained within range