Role of Canagliflozin on CD34+ Cells in Patients With Type 2 Diabetes

NCT02964585 | Completed Phase 4 Results FDA Drug

• 1 other identifier: GW-CANA-081635
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that Cana may be able to improve number and function of CD34+ endothelial progenitor cells. The investigators also propose that this expected cardiovascular benefit is independent of HbA1C reduction. Subjects will begin taking 100 mg of Cana or placebo after initial 4 weeks. Subjects will be withdrawn from the study if the medication or placebo is not tolerated.

Conditions

Type 2 Diabetes Mellitus

Keywords

Type 2 Diabetes Mellitus; Endothelial Cells; Cellular Biomarker; Endothelial Dysfunction; CD34+; Impaired renal function

Outcome Measures

Primary Outcomes (4)

• Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Protein Expression)

  To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before \[13,14\]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.

  16 weeks post Canagliflozin treatment reported

• Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Percentages)

  To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before \[13,14\]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.

  16 weeks post Canagliflozin treatment reported

• Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Counts)

  To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before \[13,14\]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.

  16 weeks post Canagliflozin treatment reported

• Gene Expression and Function Change of CD34+ Endothelial Progenitor Cells (Cell Proliferation)

  To determine whether 4 months of Canagliflozin modifies CD34+ cell number, gene expression and migration function. The investigators will obtain a total of approximately 95 mL of peripheral blood per visit. Of these 95 mL, 60-70 mL will be used to obtain CD34+ cells from mononuclear cell (MNC) population and 25-35 mL for biochemistry and plasma ELISA assays. MNC will be obtained from whole blood similar to protocols described before \[13,14\]. MNCs will be put through CD34 magnetic bead column to obtain CD34+ cells (Miltenyi Biotec). Purity of CD34+ cells, post sort, usually is above 90%, to be verified by FACS analysis.

  16 weeks post Canagliflozin treatment reported

Secondary Outcomes (14)

• Serum Endothelial Inflammatory Markers (1)

  measured at 8 and 16 (reported) weeks post treatment

• Fasting Lipid Profile

  16 weeks post Canagliflozin treatment reported (also measured at 8 weeks)

• Glycemic Control (HbA1C)

  16 weeks post Canagliflozin treatment reported

• BMI

  16 weeks post Canagliflozin treatment

• Resting Metabolic Rate (RMR)

  16 weeks post Canagliflozin treatment

Study Arms (2)

Active Arm

ACTIVE COMPARATOR

100 mg of Canagliflozin for 16 weeks

Drug: Canagliflozin

Placebo Arm

PLACEBO COMPARATOR

Placebo for 16 weeks

Drug: Placebo

Interventions

Canagliflozin DRUG

100 mg

Also known as: INVOKANA

Active Arm

Placebo DRUG

1 tablet daily for 16 weeks

Placebo Arm

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 30-70 years
• Currently treated with any combination of the following anti-diabetic therapies: metformin (1-2 grams), insulin, GLP-1 agonists, a DPP-IV inhibitor, or sulfonylureas
• Hemoglobin A1C (HbA1C) between 7.0% and 10.0%
• Body Mass Index (BMI) between 25 and 39.9 kg/m\^2 (both inclusive)

You may not qualify if:

• Type 1 diabetes
• History of hyperosmolar nonketotic coma
• History of diabetic ketoacidosis in the last 3 months
• Abnormal CBC that is judged by physician to be unsafe to enroll or low hematocrit (\<28 UNITS).
• History of pancreatitis
• History of diabetic ketoacidosis in the last 3 months
• History of cancer (except basal cell carcinoma and cancer that is cured or not active or being treated in the past 5 years)
• Heart attack or stroke within 6 months of screening
• Clinically significant coronary and/or peripheral vascular disease that would be unsafe to enroll in the study.
• Statin use started or dose change in the last 3 months
• CKD Stages 3,4 and 5
• Use of oral or injectable anti-diabetic medication other than any combination of the following anti-diabetic therapies: metformin (1-2 grams), insulin, GLP-1 agonists, a DPP-IV inhibitor, or sulfonylureas currently, or in the past 1 month.
• Use of consistent long-term steroid medication (oral, inhaled, injected) within the last 3 months
• Uncontrolled inflammatory disease, or current chronic use of anti-inflammatory drugs within the last 3 months. \*\*This will be judged on a case by case basis by the PI\*\*
• Implanted devices (e.g., pacemakers) that may interact with Body Composition scale

Sponsors & Collaborators

• George Washington University: lead
• Janssen Scientific Affairs, LLC: collaborator

Study Sites (1)

The George Washington University Medical Faculty Associates

Washington D.C., District of Columbia, 20037, United States

Location

Related Publications (13)

• Sen S, Strappe PM, O'Brien T. Gene transfer in endothelial dysfunction and hypertension. Methods Mol Med. 2005;108:299-314. doi: 10.1385/1-59259-850-1:299.

  PMID: 16028691 BACKGROUND

• Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol. 2009 Jun;296(6):F1314-22. doi: 10.1152/ajprenal.90755.2008. Epub 2009 Apr 1.

  PMID: 19339628 BACKGROUND

• Department of Health and Human Services, NIH and National Center for Chronic Disease Prevention and Health Promotion, "National Diabetes Statistics: 2007 and 2011 Fact Sheet." 2011

  BACKGROUND

• American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.

  PMID: 24357209 BACKGROUND

• Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013 Feb;24(2):302-8. doi: 10.1681/ASN.2012070718. Epub 2013 Jan 29.

  PMID: 23362314 BACKGROUND

• Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56. doi: 10.1038/ncpendmet0366.

  PMID: 17179929 BACKGROUND

• Stanton RC. Sodium glucose transport 2 (SGLT2) inhibition decreases glomerular hyperfiltration: is there a role for SGLT2 inhibitors in diabetic kidney disease? Circulation. 2014 Feb 4;129(5):542-4. doi: 10.1161/CIRCULATIONAHA.113.007071. Epub 2013 Dec 13. No abstract available.

  PMID: 24334174 BACKGROUND

• Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014 May;8(5):330-9. doi: 10.1016/j.jash.2014.02.003. Epub 2014 Feb 12.

  PMID: 24631482 BACKGROUND

• Sabyasachi Sen, Sarah Witkowski, Ann Lagoy, Ashequl M. Islam: A six-week home exercise program improves endothelial function and CD34+ circulating progenitor cells in patients with pre-diabetes. J Endocrinol Metab.2015; 5 (1-2):163-171, doi: http://dx.doi.org/10.14740/jem273w.

  BACKGROUND

• Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005 Sep 8;353(10):999-1007. doi: 10.1056/NEJMoa043814.

  PMID: 16148285 BACKGROUND

• Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007 Jun 26;115(25):3165-72. doi: 10.1161/CIRCULATIONAHA.106.687376. Epub 2007 Jun 11.

  PMID: 17562958 BACKGROUND

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

  PMID: 26378978 BACKGROUND

• Nandula SR, Kundu N, Awal HB, Brichacek B, Fakhri M, Aimalla N, Elzarki A, Amdur RL, Sen S. Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes. Cardiovasc Diabetol. 2021 Feb 13;20(1):44. doi: 10.1186/s12933-021-01235-4.

  PMID: 33581737 RESULT

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Renal Insufficiency

Interventions

Canagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Glucosides; Glycosides; Carbohydrates

Limitations and Caveats

Limitations of our pilot study may include the relatively short 16-week Canagliflozin therapy, which may be inadequate to see significant changes in certain clinical and cellular parameters. This maybe also because of the small sample size. Further studies with a larger population and longer duration may be helpful to further define the mechanisms behind our findings.

Results Point of Contact

• Title: Dr. Sabyasachi Sen
• Organization: George Washington University Medical Faculty Associates

ssen1@email.gwu.edu

202-741-2233

Study Officials

• Sabyasachi Sen, MD, PhD

  Medical Faculty Associates

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: October 6, 2016
• First Posted: November 16, 2016
• Study Start: November 1, 2016
• Primary Completion: January 1, 2020
• Study Completion: September 1, 2020
• Last Updated: December 7, 2022
• Results First Posted: December 7, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)