How canagliflozin helps protect kidneys in type 2 diabetes

Molecular Mechanisms of SGLT2 Inhibition in Diabetic Kidney Disease

We will test if taking canagliflozin for six months changes kidney cell energy-related gene activity and kidney structure in adults with type 2 diabetes and early diabetic kidney disease.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: University of Colorado, Denver (Academic / other)
• Locations: 2 sites (Aurora, Colorado and 1 other locations)
• Trial ID: NCT05507892 on ClinicalTrials.gov

What this trial studies

This open-label, non-randomized mechanistic Phase 2 trial will enroll 40 adults with type 2 diabetes and early diabetic kidney disease who will take 100 mg canagliflozin daily for six months in addition to standard care. Participants will undergo paired research kidney biopsies at baseline and after six months, with single-cell RNA sequencing of biopsy tissue as the primary outcome to measure intrarenal transcripts related to energy metabolism. Secondary measures include morphometric analysis of biopsy tissue, GFR and renal plasma flow measurements, and multiparametric kidney MRI performed near the time of each biopsy to link imaging findings with molecular and structural changes. The trial is conducted at the University of Colorado Denver (Aurora, CO) and the University of Michigan (Ann Arbor, MI).

Who should consider this trial

Good fit: Adults aged 18–80 with type 2 diabetes for at least 3 years, eGFR between 45 and 90 ml/min/1.73m2, urinary albumin-to-creatinine ratio under 3000 mg/g, and willingness to undergo paired kidney biopsies and imaging are ideal candidates.

Not a fit: People with advanced kidney disease (eGFR <45), active liver disease, uncontrolled cardiovascular disease, or those unwilling/unable to undergo kidney biopsy or travel to the study sites are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, the findings could explain how canagliflozin protects kidneys and guide more targeted use or development of therapies to slow diabetic kidney disease.

How similar studies have performed: Large outcome trials of SGLT2 inhibitors, including canagliflozin, have shown kidney protection, but paired biopsy-based molecular studies to define intrarenal mechanisms remain largely untested.

Eligibility 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.
* Conditions likely to interfere with informed consent or compliance with the protocol.
* Single kidney; any condition with a single kidney
* Kidney cortex \<1 cm (both kidneys)
* Kidney length \<8 cm (both kidneys)

Where this trial is running

Aurora, Colorado and 1 other locations

• University of Colorado Denver — Aurora, Colorado, United States (Recruiting)
• University of Michigan — Ann Arbor, Michigan, United States (Recruiting)

Study contacts

• Principal investigator: Petter Bjornstad, MD — University of Washington
• Study coordinator: Jessica Kendrick, MD, MPH

Conditions Type 2 Diabetes; Diabetic Kidney Disease