Canagliflozin and Myocardial Fibrosis

NCT05367063 | Completed Phase 4

• 1 other identifier: ZSE-202112
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

Recently, large clinical intervention studies have demonstrated the cardiovascular protective effects on of sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin, dapagliflozin, and canagliflozin in reduction of cardiovascular and all-cause mortality, coincident with a significant reduction in heart failure hospitalizations. Therefore, SGLT2i had been recommended as a therapeutic drug for diabetic patients to reduce the occurrence of cardiovascular events. However, the mechanism of these benefits remains unclear at the present time. Myocardial fibrosis is not only an important physiopathological mechanism of heart failure, but also has been shown to be closely associated with the risk of heart failure-related hospitalization and death, especially in patients with T2D. However, whether SGLT2i can exert cardioprotective effects by improving myocardial fibrosis remains to be further investigated. In recent years, the development of cardiac magnetic resonance (CMR) technology enables to detect focal and diffuse fibrosis in myocardial tissue, which makes it possible to systematically explore the role of SGLT2i on myocardial fibrosis. Although several studies including EMPA-HEART, SUGAR-DM-HF have explored the effects of SGLT2i on cardiac structure and function, these studies didn't reach consistent results. In addition, more scarce studies have investigated the effects of SGLT2i on both focal and diffuse fibrosis. At present, whether SGLT2i treatment can change the relevant indicators of myocardial fibrosis in people with diabetes and cardiovascular risk factors has not yet been reported. In addition, previous studies mainly focus on empagliflozin and dapagliflozin, and studies on canagliflozin are still very scarce. Therefore, this study intends to explore the effects of canagliflozin on myocardial fibrosis and other structures and functions of the heart in patients with type 2 diabetes mellitus and high cardiovascular risk factors.

Conditions

Type 2 Diabetes; Cardiovascular Risk

Keywords

SGLT2 inhibitor; Canagliflozin; Type 2 diabetes mellitus; Myocardial fibrosis; Cardiac magnetic resonance; Cardiovascular risk

Outcome Measures

Primary Outcomes (1)

• Change in myocardial fibrosis

  The rate of ventricular extracellular volume and late gadolinium enhancement measured by MRI

  26 weeks since the randomization

Secondary Outcomes (2)

• Change in Left Ventricle (LV) Structure/Function

  26 weeks since the randomization

• Change in resting mocardial blood flow

  26 weeks since the randomization

Study Arms (2)

Canagliflozin group

ACTIVE COMPARATOR

On the basis of the original metformin medication, the experimental group took canagliflozin 1 tablet (100 mg) orally once a day (qd) before the first meal of the day, and the dosing cycle lasts 6 months.

Drug: Canagliflozin 100mg or Sitagliptin 100mg

Sitagliptin group

PLACEBO COMPARATOR

On the basis of the original metformin medication, the experimental group took Sitagliptin 1 tablet (100 mg) orally once a day (qd) before the first meal of the day, and the dosing cycle lasts 6 months.

Drug: Canagliflozin 100mg or Sitagliptin 100mg

Interventions

Canagliflozin 100mg or Sitagliptin 100mg DRUG

Eligible type 2 diabetes patients at high risks of cardiovascular diseases will be randomly assigned by a 1:1 ratio to either Canagliflozin 100 mg once daily or Sitagliptin 100 mg once daily.

Canagliflozin group; Sitagliptin group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• History of type 2 diabetes;
• Haemoglobin A1c ≥7.0% and \< 10.5%;
• Patients who have received a stable dose of metformin or metformin combined with insulin secretagogues and/or insulin therapy for 4 weeks before enrollment;
• Those who met at leat one of the following criteria:
• Patients with at least 3 of the folllowing risk factors: (1) male \>55 years old, or female \> 65 years old; (2) BMI≥25 kg/m2; (3) hypertension; (4) dyslipidemia; (5) current smoker (Brinkman index ≥ 200;
• Any of the following signs of target organ damage are present: (1) albuminuria (ACR≥300mg/g); (2) 45 ml/min/1.73 m2 ≤eGFR\<90 ml/ min/1.73 m2; (3) Left ventricular hypertrophy or coupled with retinopathy.

You may not qualify if:

• Female subjects who are pregnant, lactating or of child bearing potential, or pre-menopausal women. (Menopause will be determined by patient and physician history;
• Subjects currently treated with SGLT2 inhibitors, GLP1 receptor agonist, or sitagliptin;
• Significant allergy or known intolerance to Canagliflozin or Sitagliptin;
• History of hypovolemia, amputation, peripheral vascular disease, diabetic foot ulcers;
• History of diagnosed cardiovascular diseases, including myocardial infarction, hospitalization for unstable angina pectoris, cerebral infarction (ischemic stroke), coronary artery bypass grafting, percutaneous coronary intervention (with or without stents) Implantation), peripheral vascular reconstruction (angioplasty or surgery), heart failure, arrhythmia, heart valve disease;
• AST or ALT ≥ 3 times the upper limit of normal;
• eGFR \<45 ml/min/1.73 m2；
• type 1 diabetes;
• Diabetic ketosis or diabetic hyperosmolar coma;
• History of respiratory disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension, etc.);
• Existing hypertensive emergency (systolic/diastolic blood pressure exceeding 180/120mmHg) at the time of enrollment, or evaluated For refractory hypertension (after the use of sufficient doses of 3 antihypertensive drugs, the systolic blood pressure is still\> 140 or Diastolic blood pressure\> 90mmHg);
• Known impaired gastrointestinal function or gastrointestinal diseases that may significantly affect the absorption of the test drug, such as: diagnosed active ulcers (Forrest grade II and below), inflammatory bowel disease, malabsorption related diseases, and non-absorbent diseases. Controlled diarrhea, gastrointestinal surgery (such as bariatric surgery);
• Patients with diagnosed malignant tumors;
• Participate in other clinical trials within 3 months;
• Other creteria that were not eligible to participate in the clinical trial.

Sponsors & Collaborators

• Shanghai Zhongshan Hospital: lead

Study Sites (1)

Zhongshan Hospital, Fudan University

Shanghai, Shanghai Municipality, 200000, China

Location

Related Publications (10)

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  PMID: 31518657 BACKGROUND

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  PMID: 31167558 BACKGROUND

• Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12.

  PMID: 28605608 BACKGROUND

• Hudsmith LE, Petersen SE, Tyler DJ, Francis JM, Cheng AS, Clarke K, Selvanayagam JB, Robson MD, Neubauer S. Determination of cardiac volumes and mass with FLASH and SSFP cine sequences at 1.5 vs. 3 Tesla: a validation study. J Magn Reson Imaging. 2006 Aug;24(2):312-8. doi: 10.1002/jmri.20638.

  PMID: 16795076 BACKGROUND

• Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Juni P, Zinman B, Connelly KA. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019 Nov 19;140(21):1693-1702. doi: 10.1161/CIRCULATIONAHA.119.042375. Epub 2019 Aug 22.

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  PMID: 32578850 BACKGROUND

• Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, Berry C, Chong V, Coyle L, Docherty KF, Dreisbach JG, Labinjoh C, Lang NN, Lennie V, McConnachie A, Murphy CL, Petrie CJ, Petrie JR, Speirits IA, Sourbron S, Welsh P, Woodward R, Radjenovic A, Mark PB, McMurray JJV, Jhund PS, Petrie MC, Sattar N. Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation. 2021 Feb 9;143(6):516-525. doi: 10.1161/CIRCULATIONAHA.120.052186. Epub 2020 Nov 13.

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  PMID: 32245746 BACKGROUND

• Yan H, Liu J, Zhang Z, Chen S, Chang X, Jin H, Li X, Chen Y, Chen Y, Zeng M. Canagliflozin attenuates CMR-quantified myocardial fibrosis in individuals with type 2 diabetes mellitus at high cardiovascular risk: a randomised open-label controlled trial. Diabetologia. 2026 Feb 24. doi: 10.1007/s00125-026-06682-w. Online ahead of print.

  PMID: 41735586 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Canagliflozin; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Xiaoying Li, PhD

  Fudan University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The outcome evaluators only know the subjects' numbers and have no knowledge of other clinical information about the subjects.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: On the basis of a stable dose of metformin, the test group was treated with Canagliflozin tablets (SGLT2 inhibitor), and the control group was treated with Sitagliptin tablets (DPP-4 inhibitor).

Study Record Dates

• First Submitted: December 7, 2021
• First Posted: May 10, 2022
• Study Start: January 5, 2022
• Primary Completion: December 31, 2024
• Study Completion: March 20, 2025
• Last Updated: December 16, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: No time limited.
• Access Criteria: Anyone can access the Statistical Analysis Plan (SAP).

Locations

CN (1)