- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02481479
Saxagliptin and Cardiac Structure and Function (SCARF)
SCARF: Saxagliptin on CArdiac StRucture and Function
Study Overview
Status
Intervention / Treatment
Detailed Description
The cardiovascular safety and potential cardioprotective effects of diabetes drugs have been the focus of recent research. Currently, the Food and Drug Administration (FDA) requires all new anti-diabetic drugs to demonstrate no important increase in cardiovascular adverse events before approval.
Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are oral incretin-based agents that increase glucagon-like peptide-1 (GLP-1) level, with proven anti-hyperglycemic effects and are increasingly used in the management of type 2 diabetes. In a rat model of diabetes and myocardial infarction, sitagliptin treatment improved passive left ventricular compliance, increased endothelial cell density, reduced myocyte hypertrophy and collagen abundance. GLP-1 and DDP-4 inhibition with vildagliptin improve cardiac function, cardiac remodeling, and survival in animal models of pressure-overload and chronic heart failure. However, in another study of post-MI cardiac remodeling in mice, vildagliptin failed to show any early or late protective effects on cardiac function.
Some clinical studies suggest that GLP-1 infusion is associated with an absolute increase in left ventricular ejection fraction (LVEF) in patients with heart failure, although data are conflicting. The GLP-1 receptor analog, exenatide may reduce infarct size in patients with myocardial infarction but does not improve LVEF.
The Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome EXAMINE trial randomized assigned 5340 patients with type 2 diabetes and recent acute coronary syndrome to alogliptin or placebo, and found no increase in adverse cardiovascular events in the alogliptin group. In SAVOR-TIMI 53, 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events were randomized to receive saxagliptin or placebo. Over a median follow-up of 2.1 years, the primary composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke did not differ significantly between the 2 groups (P=0.99 for superiority; P<0.001 for noninferiority). However, patients in the saxagliptin group were more likely to be hospitalized for heart failure, which was not ascertained in the EXAMINE trial. Furthermore, the Sitagliptin Cardiovascular Outcome Study (TECOS), which examined the DPP4i sitagliptin versus placebo in high risk patients for a cardiovascular event demonstrated cardiovascular safety (P<0.001 for non inferiority), and there was no signal for excess heart failure hospitalizations.
Cardiac magnetic resonance imaging (CMR) has emerged as the "gold standard" for measuring LV volume, mass, and ejection fraction. LV volume measurements by cardiac MRI do not rely on geometric assumptions. CMR measurements have excellent intra-observer, inter-observer, and inter-study variability, which were superior to other imaging techniques. The high inter-study reproducibility of CMR affords a substantial reduction in the required sample size to demonstrate even small changes in LV volume, LV mass or LVEF, or conversely, to reliably exclude clinically important changes. Furthermore, CMR tagging allows detailed and quantitative assessment of regional LV diastolic and systolic function. For example, in the Multiethnic Study of Atherosclerosis (MESA), CMR can detect subtle alterations in global and regional LV functions in patients with traditional and novel cardiovascular risk factors. Although prior studies have failed to demonstrate any beneficial effects of improved glycemic control on myocardial function, CMR promises to be a more sensitive and accurate technique.
Accordingly, the investigators propose to use CMR to examine the cardiac structure, global and regional function among patients with type 2 diabetes treated with saxagliptin.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Ontario
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Toronto, Ontario, Canada, M5B1W8
- St Michael's Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Adult (≥18 years old) men or women with type 2 diabetes diagnosed for ≥ 6 months
- HbA1c 7.5 - 9.5%
- Receiving background therapy with metformin (additional anti-hyperglycemic agents are permitted)
- Clinical decision to initiate saxagliptin to improve glycemic control, as per treating physician
Exclusion Criteria:
- GLP-1 receptor agonist or DPP4 inhibitor treatment within the past 6 months, or known intolerance
- eGFR <30
- Baseline LVEF <40%
- NYHA Class III-IV or recent hospitalization for decompensated HF (<3 months)
- Unstable coronary syndromes or recent revascularization within the past 3 months, or planned revascularization in the next 6 months
- Significant (moderate or severe, or symptomatic) valvular disease
- Pregnancy/childbearing potential
- Routine contraindications to CMR Subjects who drop out from the study will have a repeat CMR examination as soon as possible after drug discontinuation.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Single group -Paired comparison
Saxagliptin 2.5mg or 5mg od
|
Eligible patients will undergo baseline CMR, commence treatment and then after 6 months undergo repeat CMR
Other Names:
Eligible patients will undergo baseline echocardiogram, commence treatment and then after 6 months undergo repeat echocardiogram
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The change in LVEF from baseline to 6 months
Time Frame: baseline, 6 months
|
assess LVEF at baseline and at 6 months following treatment.
CMR based LVEF assessment using Cvi 42.
|
baseline, 6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The change in E/e' from baseline to 6 months
Time Frame: baseline, 6 months
|
Echocardiography assessed E and E', to determine ratio, and assess change from baseline to 6 months.
|
baseline, 6 months
|
change in class indicators of signs and symptoms of heart failure at each visit
Time Frame: baseline, 6 months
|
assess NYHA class at baseline and at 6 months
|
baseline, 6 months
|
Change in log-scale in NT-pro BNP
Time Frame: baseline, 6 months
|
assess NT-ProBNP at baseline and at 6 months
|
baseline, 6 months
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: Subodh Verma, MD, Professor of Surgery
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Protease Inhibitors
- Incretins
- Dipeptidyl-Peptidase IV Inhibitors
- Saxagliptin
Other Study ID Numbers
- 14-267
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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