Renal Mechanism of SGLT2 Inhibition

• Status: Recruiting
• Trial end date: 2024-07-15
• Target enrollment: 0
• Participant gender: All

Summary

Canagliflozin is an oral drug which is currently approved for use in patients with type 2 diabetes by the US Food and Drug Administration (FDA). Canagliflozin acts by increasing salt and sugar loss in the urine, and has shown to protect heart, kidney, and blood vessel function in patients with type 2 diabetes. However, it is unknown how canagliflozin protects the kidneys from disease. Therefore, this study plans to learn more about how canagliflozin works to protect against diabetic kidney disease in adults with type 2 diabetes. This study will use state-of-the-art kidney imaging, kidney biopsies and detailed testing of kidney function to determine the mechanisms of protection afforded by canagliflozin.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Colorado, Denver
• Collaborators: Boston Medical Center; Brigham and Women's Hospital; University of Michigan
• Treatments: Canagliflozin

Criteria

Inclusion Criteria:

• Aged 18-80 years. The lower age limit was set so renal function test results would not 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 equation using 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 maximum tolerable dose for at least 3 months prior to the study baseline examination.

• Participants receiving a GLP-1 receptor agonist must have been receiving the drug for 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 cardiovascular disease, symptomatic peripheral vascular disease, (i.e. intermittent claudication), pulmonary diseases (including uncontrolled asthma and restrictive or obstructive lung disease requiring therapy), renal-urinary disorders (calculi, urinary tract obstruction, 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 blood pressure ≥150 or diastolic ≥90 mm Hg)

• Hematuria of unknown etiology.

• Prior to entry into the study, any participant with hematuria should be evaluated, the etiology established and documented, and treatment rendered as appropriate.

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

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

• Pregnancy.

• SGLT2 inhibitors are not recommended during the second or third trimester of pregnancy. Moreover, we do not wish to expose pregnant women to conscious sedation that is used during the kidney biopsies or to the intravenous filtration markers iohexol and p-aminohippurate needed for the renal clearance studies. Women of childbearing potential must have a negative pregnancy test prior to entry and every 2 months during the study and agree to using an effective form of contraception throughout the study, such as the oral contraceptive pill or an intrauterine device. Women who are planning a pregnancy in the next three years will be excluded.

• Known hypersensitivity to canagliflozin or iodine.

• Bleeding disorders or requirements for anticoagulation or platelet inhibitors which cannot be safely interrupted, since kidney biopsies cannot be performed safely in these 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 biopsy examination.

• History of osteoporotic fracture.

• History of lower-limb amputation irrespective of etiology.

• Conditions likely to interfere with informed consent or compliance with the protocol.