Impact of a Short-term Treatment With Canagliflozin (Canacardia-HF) (Canacardia)

Subclinical Inflammation, Myocardial Function and Fatty Acid Metabolism in Patients With Type 2 Diabetes and Heart Failure: Impact of a Short-term Treatment With Canagliflozin - a Pilot Study

It is a mechanistic proof-of-concept study to demonstrate how SGLT-2 inhibitors (Canagliflozin) may have a beneficial role on cardiac energetic efficiency.

Patients with type 2 diabetes and with HF diagnosed for at least 3 months will be selected. The participants will be randomized to a double-blind, crossover 2-week placebo vs. Cana 100 mg once daily, an interventional trial with a one-month washout period in between.

At the term of the two-week placebo and canagliflozin treatment periods (visits 2 and 4), each participant will undergo an identical postprandial metabolic study with positron emission tomography (PET) and stable isotopic tracer methods.

Study Overview

• Status: Withdrawn
• Conditions: Heart Failure; Type2 Diabetes
• Intervention / Treatment: Drug: Placebo oral capsule; Radiation: PET imaging; Drug: Canagliflozin 100mg

Detailed Description

Non-invasive Positron Emission Tomography (PET) imaging method allows to measure myocardial uptake and organ-specific partitioning of dietary fatty acids (DFA). It allows to study kidney, liver, skeletal muscles and adipose tissues DFA utilization, whole body fatty acid turnover and oxidation rates, myocardial oxidative metabolism and left ventricular (LV) function that are other likely targets of SGLT-2 inhibitors. Thus, the PET is ideal to verify the very interesting hypothesis that, increase in liver fatty acid utilization and/or adipose tissue dietary fatty acid uptake, may lead to reduced cardiac utilization of fatty acids and improved cardiac energetic efficiency.

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• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HbA1c 7.5 -10.5%;
• LVEF < 40%;
• NYHA class 2 or 3;
• NT pro-BNP level > 600 pg/mL;
• Being on a stable-dose metformin therapy max 2500 mg/day or other hypoglycemic therapy and RAAS-blocking agents for at least 8 weeks;
• Being on optimal and stable-doses of heart failure medication including diuretics for at least 4 weeks;

Exclusion Criteria:

• age <18 yo;
• NYHA class 4;
• Treatment with a fibrate or thiazolidinedione;
• Unstable or advanced renal failure;
• Unstable or new medical or surgical condition within the past 3 months;
• Heart failure caused by active inflammatory condition such as sarcoidosis or any form of myocarditis;
• History of diabetic ketoacidosis;
• Not on a stable regimen for at least 8 weeks before the screening visit;
• Female of child-bearing potential who is pregnant, breast feeding or intends to become pregnant or pre-menopausal female with a positive serum pregnancy test at the time of enrollment;
• Patients post bariatric surgery, or on weight loss medication;
• Contraindications to metformin, including allergy or intolerance;
• Hospitalization for heart failure within the 60 days prior to enrollment;
• Admission for an acute coronary syndrome, percutaneous coronary intervention, or cardiac surgery within the 60 days prior to enrollment;
• Planned cardiovascular revascularization (percutaneous intervention or surgical) or major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, cardiac transplantation, or any other surgery requiring thoracotomy) within the 90 days after enrollment;
• Patients who are volume depleted based upon physical examination at the time of enrollment;
• Chronic disabling illness;
• History of substance abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Treatment 1; placebo oral capsule will be administered once daily, for 2 weeks	Drug: Placebo oral capsule; 2-week intervention; Radiation: PET imaging; 1 day postprandial metabolic protocol at the end of treatment: CT scan followed by dynamic and pancorporel imaging
Experimental: Treatment 2; Canagliflozine 100mg once daily, for 2 weeks	Radiation: PET imaging; 1 day postprandial metabolic protocol at the end of treatment: CT scan followed by dynamic and pancorporel imaging; Drug: Canagliflozin 100mg; 2-week intervention; Other Names: Invokana

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change to be observed with canagliflozin on myocardial dietary fatty acid uptake	will be assessed using oral administration of 18-fluoro-thiaheptadecanoic acid ([18F]-FTHA) with sequential dynamic. PET/CT scanning.	3 months
Change to be observed with canagliflozin on whole-body partitioning.	will be assessed using oral administration of 18-fluoro-thiaheptadecanoic acid ([18F]-FTHA, with static PET/CT scanning	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
myocardial and liver NEFA uptake	using PET with [11C]-palmitate	3 months
NEFA oxidative rate	using PET with [11C]-acetate	3 months
plasma NEFA turnover	using i.v. infusion of [U-13C]-palmitate	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity	will be determined using the HOMA-IR (based on fasting insulin and glucose levels)	1 year
Insulin secretion rate	will be assessed using deconvolution of plasma C-peptide with standard Cpeptide kinetic parameters	1 year
β-cell function	will be assessed by calculation of the disposition index (DI) that is insulin secretion in response to the ambient insulin	1 year
hormonal response	will be determined using a multiplex assay system	1 year
Biomarkers	Assays will be performed using the BIOPLEX	1 year
body composition	DXA	3 months

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: Janssen Inc.
• Investigators: Principal Investigator: André C. Carpentier, Université de Sherbrooke

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2017
• Primary Completion (Anticipated): November 1, 2018
• Study Completion (Anticipated): January 1, 2019

Study Registration Dates

• First Submitted: September 26, 2017
• First Submitted That Met QC Criteria: September 28, 2017
• First Posted (Actual): September 29, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 15, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Heart Failure; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Canagliflozin
• Other Study ID Numbers: 28431754DIA4029

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No