Mechanism of SGLT2 Inhibition in the Kidney

Molecular Mechanisms of SGLT2 Inhibition in Diabetic Kidney Disease

The goal of this open-label, non-randomized clinical trial is to determine what effects, if any, an FDA-approved drug class known as SGLT2 inhibitors (Canagliflozin or INVOKANA) has any protective effects on kidney function in Type 2 diabetes. We are looking for participants 18-80 years of age, who have had a clinical diagnosis of Type 2 diabetes for ≥ 3 years.

Participants will be asked to sign a consent and complete a screening visit prior to study entry including the following procedures for this study:

Consent and Screening:

• Laboratory tests to determine baseline health
• Ultrasound to measure kidney size and ensure presence of 2 functioning kidneys

Month 0:

• Study entry kidney MRI (day 0)
• Study entry kidney biopsy (within 30 days of MRI)
• Study entry visit for dispensing 100 mg/daily Canagliflozin medication 3 month supply

Month 3:

• Study visit to dispense remaining 3 months of 100 mg/daily Canagliflozin medication
• Review of systems

Month 6:

• Follow-up kidney MRI
• Follow-up kidney biopsy

Study participants will also be requested to provide blood and urine samples for biobanking purposes. They will also be provided the opportunity to provide a stool sample at two time points, as well as the option to participate in a related study collecting samples to create induced Pluripotent Stem Cells (iPSCs).

Participants will be compensated for their time and loss of work time, additionally, a nominal additional compensation for optional stool and iPSC samples.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Kidney Disease; Type 2 Diabetes
• Intervention / Treatment: Drug: SGLT2 inhibitor

Detailed Description

The purpose of this protocol is to examine the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin on intrarenal transcripts of energy metabolism in adults with type 2 diabetes and early diabetic kidney disease (DKD) via an open-label non-randomized mechanistic trial. This trial will enroll 40 participants who will receive 100 mg of canagliflozin daily for six (6) months in addition to standard of care. The primary objective of this study is to determine whether canagliflozin affects intrarenal transcripts of energy metabolism in adults with type 2 diabetes and early DKD.

The primary outcomes measure will be change in transcripts as assessed by single-cell RNA sequencing of kidney biopsy specimens obtained at study entry and after 6 months of study drug. Secondary outcomes include assessing the effects of canagliflozin on structural progression of DKD assessed by morphometric examination of kidney tissue specimens from the paired research biopsies. Additional secondary outcomes include measures of glomerular filtration rate (GFR) and renal plasma flow (RPF) as well as multiparametric kidney MRI. Magnetic resonance imaging of the kidneys will be performed prior to each biopsy to correlate the molecular and structural damage seen at kidney biopsy with the level of perfusion, oxygen availability and fibrosis detected by imaging. Imaging of the kidneys will be done as near to the time of each kidney biopsy as possible. Participants will be followed annually after completion of the mechanistic clinical trial until death or development of end-stage kidney disease.

Participants will be followed for potential adverse events for an additional two months post six-month biopsy.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Chrysta C Lienczewski, BS; Phone Number: 734-615-5021; Email: boridley@umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Chrysta C Lienczewski, BS; Phone Number: 734-615-5021; Email: boridley@umich.edu
      • Principal Investigator: Markus Bitzer, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.
• Participants must meet the current clinical guidelines for prescribing SGLT2 inhibitors, 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 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 and ongoing treatment with SGLT2 inhibitors
• 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.. 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.
• Known solitary kidney
• Size of one or both kidneys on ultrasound < 9 cm (small kidney size is concerning for renal atrophy due to underlying kidney disease) or > 2 cm discrepancy between left 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 significant stone disease

  1. Inclusion possible after this has been obtained within range

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: SGLT2i Arm	Drug: SGLT2 inhibitor; All participants will be receive 100 mg/daily doses of Canagliflozin (INVOKANA) for 6 months. Canagliflozin is a Sodium-glucose cotransporter 2 (SGLT2) inhibitor; Other Names: Invokana; Canagliflozin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular basement membrane (GBM) width and mesangial expansion	Measured by morphometric examination of kidney tissue	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney Transcript Changes	Molecular changes measured by change in transcripts as assessed by single-cell RNA sequencing of kidney biopsy specimens	6 month follow-up

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: University of Colorado, Denver
• Investigators: Principal Investigator: Markus Bitzer, MD, Professor of Internal Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): February 28, 2028

Study Registration Dates

• First Submitted: February 26, 2024
• First Submitted That Met QC Criteria: February 26, 2024
• First Posted (Actual): March 4, 2024

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Canagliflozin; SGLT2i; SGLT2 inhibitor; Kidney biopsy; INVOKANA; Kidney MRI; FDA-approved; Renal biopsy; Renal MRI
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Complications; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pharmacologic Actions; Chemical Actions and Uses; Carbohydrates; Glucosides; Glycosides; Thiophenes; Sodium-Glucose Transporter 2 Inhibitors; Canagliflozin
• Other Study ID Numbers: HUM00222335

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No