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Saxagliptin and Cardiac Structure and Function (SCARF)

This study is currently recruiting participants.
Verified October 2016 by St. Michael's Hospital, Toronto
Sponsor:
ClinicalTrials.gov Identifier:
NCT02481479
First Posted: June 25, 2015
Last Update Posted: October 17, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto
  Purpose
Diabetes is associated with a substantially increased risk of heart failure, which is associated with substantial morbidity and mortality. Despite the development of new therapeutic strategies to improve glycemic control, recent clinical data from the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study observed an unexpected finding of an excess of adjudicated heart failure hospitalizations. This excess occurred in the setting of pre-existing heart failure (HF) hospitalization and in those with elevated biomarkers for heart failure such as N terminal pro Brain type natriuretic peptide (NT-pro BNP). A wealth of preclinical data did not suggest a mechanistic basis for an excess of heart failure events, however these preclinical studies primarily focused upon prevention based strategies as opposed to regression studies once established heart failure was present. This proposal seeks to understand if and how dipeptidyl peptidase-4 inhibitors (DPP4i,specifically saxagliptin) may influence the development of heart failure, by evaluating changes in cardiac structure and function using cardiac magnetic resonance imaging (MRI).

Condition Intervention Phase
Diabetes Mellitus, Non-Insulin-Dependent Heart Failure Drug: Saxagliptin Drug: saxagliptin Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: SCARF: Saxagliptin on CArdiac StRucture and Function

Resource links provided by NLM:


Further study details as provided by St. Michael's Hospital, Toronto:

Primary Outcome Measures:
  • The change in LVEF from baseline at 6 months [ Time Frame: baseline, 6 months ]

Secondary Outcome Measures:
  • Change in echocardiography parameters [ Time Frame: baseline, 6 months ]
  • The change in plasma volume from baseline at 6 months [ Time Frame: baseline, 6 months ]
  • change in class indicators of signs and symptoms of heart failure at each visit [ Time Frame: baseline, 6 months ]
  • Change in log-scale in NT-pro BNP [ Time Frame: baseline, 6 months ]
  • Change in clinical composite score (NYHA and global patient assessment score) time frame [ Time Frame: baseline, 6 months ]

Estimated Enrollment: 40
Study Start Date: June 2015
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Single group -Paired comparison
Saxagliptin 2.5mg or 5mg od
Drug: Saxagliptin
Eligible patients will undergo baseline CMR, commence treatment and then after 6 months undergo repeat CMR
Other Name: Onglyza
Drug: Saxagliptin
Eligible patients will undergo baseline echocardiogram, commence treatment and then after 6 months undergo repeat echocardiogram
Other Name: Onglyza
Drug: saxagliptin
Eligible patients will undergo baseline venipuncture, commence treatment and then after 6 months undergo repeat venipuncture
Other Name: Onglyza

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult (≥18 years old) men or women with type 2 diabetes diagnosed for ≥ 6 months
  2. HbA1c 7.5 - 9.5%
  3. Receiving background therapy with metformin (additional anti-hyperglycemic agents are permitted)
  4. Clinical decision to initiate saxagliptin to improve glycemic control, as per treating physician

Exclusion Criteria:

  1. GLP-1 receptor agonist or DPP4 inhibitor treatment within the past 6 months, or known intolerance
  2. eGFR <30
  3. Baseline LVEF <40%
  4. NYHA Class III-IV or recent hospitalization for decompensated HF (<3 months)
  5. Unstable coronary syndromes or recent revascularization within the past 3 months, or planned revascularization in the next 6 months
  6. Significant (moderate or severe, or symptomatic) valvular disease
  7. Pregnancy/childbearing potential
  8. Routine contraindications to CMR Subjects who drop out from the study will have a repeat CMR examination as soon as possible after drug discontinuation.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02481479


Contacts
Contact: Kim Connelly, MBBS 14168645201 connellyk@smh.ca
Contact: Paul Sandhu, MD Sandhup@smh.ca

Locations
Canada, Ontario
St Michael's Hospital Recruiting
Toronto, Ontario, Canada, M5B1W8
Sponsors and Collaborators
St. Michael's Hospital, Toronto
Investigators
Study Director: Subodh Verma, MD Professor of Surgery
  More Information

Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT02481479     History of Changes
Other Study ID Numbers: 14-267
First Submitted: June 16, 2015
First Posted: June 25, 2015
Last Update Posted: October 17, 2016
Last Verified: October 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Diabetes Mellitus
Heart Failure
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
Saxagliptin
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents