Cardiovascular effects of empagliflozin in diabetes mellitus
| ISRCTN | ISRCTN82391603 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN82391603 |
| IRAS number | 241152 |
| Secondary identifying numbers | 38480, IRAS 241152 |
- Submission date
- 08/10/2018
- Registration date
- 16/10/2018
- Last edited
- 25/08/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English summary of protocol
Background and study aims
The prevalence of type 2 diabetes in the UK has more than doubled in the past 20 years and is expected to continue to rise. Despite improvements in diagnosis and treatment, the life expectancy of patients with type 2 diabetes remains significantly lower than that of the general population. Type 2 diabetes is associated with an increased cardiovascular (heart disease) risk compared to the general population, even after adjustment for other risk factors, and this risk has proved difficult to modify. Older medications aimed at improving blood sugar control, including sitagliptin, have shown no significant improvement in cardiovascular outcomes. Recently, a new medication, empagliflozin, has been shown to decrease both cardiovascular and all-cause mortality and decrease heart failure admissions in patients with type 2 diabetes and known cardiovascular disease. The mechanisms by which empagliflozin causes this reduction in heart failure and cardiovascular mortality are as yet unknown. The aim of this study is to determine the effects of empagliflozin on the heart in a population of patients with similar characteristics as studied in recent clinical trials.
Who can participate?
Patients aged 18-84 with known cardiovascular disease and recent heart attack (myocardial infarction), and with known type 2 diabetes
What does the study involve?
Participants receive sitagliptin and empagliflozin over two periods of 3 months and undergo tests including cardiac magnetic resonance imaging (MRI) of scar (extracellular fibrosis) and blood flow to the heart muscle, as well as assessment of diabetes status including blood tests. The aim is to find out whether empagliflozin treatment has any effects on the heart that are measurable with MRI.
What are the possible benefits and risks of participating?
There will be no direct clinical benefit to individual patients. This will be made clear at the start of the study. However, the results may show which diabetic medication is best for the control of their blood sugars, informing long-term prescribing. There are no direct risks to the patient from participating in this study. Some patients can find blood tests painful or may experience claustrophobia in the MRI scanner. Every effort will be made to reduce these sensations, as per normal clinical routine in MRI scanning, but if a participant cannot tolerate the procedure, the scan will be stopped immediately.
Where is the study run from?
Leeds General Infirmary (UK)
When is the study starting and how long is it expected to run for?
April 2018 to June 2022
Who is funding the study?
British Heart Foundation (UK)
Who is the main contact?
Dr Kathryn Richards
K.H.Richards@leeds.ac.uk
Contact information
Scientific
LICAMM
LIGHT Laboratories
University of Leeds
6 Clarendon Way
Leeds
LS2 9LU
United Kingdom
 ORCID ID |
0000-0001-9539-3123 |
|---|---|
| Phone | +44 (0)113 3928250 |
| K.H.Richards@leeds.ac.uk |
Study information
| Study design | Randomised; Both; Design type: Treatment, Drug, Validation of investigation/therapeutic procedures |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN82391603_PIS_v1.2_19Jun18.docx |
| Scientific title | Cardiovascular effects of empagliflozin in diabetes mellitus |
| Study acronym | CEED |
| Study objectives | The trialists hypothesise that empagliflozin treatment is associated with changes in myocardial blood flow and myocardial fibrosis as measured by CMR, independently of blood sugar control. |
| Ethics approval(s) | Yorkshire & Humber- South Yorkshire Research Ethics Committee, 19/06/2018, ref: 18/YH/0190 |
| Health condition(s) or problem(s) studied | Heart disease in patients with type 2 diabetes and previous myocardial infarction |
| Intervention | This is a crossover study to characterise the cardiac effects of sitagliptin and empagliflozin on CMR imaging biomarkers and glycaemic status in patients with type 2 diabetes with a history of myocardial infarction. The trialists plan to recruit 60 patients with a diagnosis of diabetes and known heart disease. All participants will have HbA1c (a monitor of blood sugar control) levels within a range where an additional medication for diabetes would usually be considered. They will continue on their current diabetes medications throughout the trial. All participants will undergo three CMR scans. A baseline scan will be carried out, followed by randomisation to either sitagliptin (100 mg once daily) or empagliflozin (10 mg once daily) by mouth for 3 months, then a second CMR scan, followed by 3 months therapy with the other medication and a final CMR scan. In addition, blood tests and blood glucose monitoring with a Libre Pro will be carried out 2 weeks before each CMR scan. The Libre Pro is a small patch that sticks to the patient's skin, usually the upper arm, and remains in place for up to 2 weeks. It provides results for continuous blood sugar monitoring over that time, then this information is downloaded after removal. Blood tests will include fasting glucose and insulin levels, HbA1c (a marker of diabetes control), a full blood count (FBC) and eGFR (a marker of kidney function). In total, this would amount to 7 visits for each participant. The entire visit will take around 2 hours when a CMR scan takes place (3 visits). Visits for blood tests and blood sugar monitoring would take approximately 30 minutes. Patients will be asked to record on a patient diary that they have taken the study medication each day. These scans will be for research purposes only. However, the results of blood sugar control and HbA1c with each medication will be available to the GP and could help chose which medication to continue in the long term. CMR scans will involve use of adenosine as a stress agent to assess perfusion reserve, and the use of standard contrast agent to assess the amount of scarred myocardium. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Sitagliptin, empagliflozin |
| Primary outcome measure | Myocardial perfusion reserve in remote myocardium, measured by cardiac MRI at baseline, 12 and 24 weeks |
| Secondary outcome measures | 1. Myocardial perfusion reserve in infarcted territory 2. Extracellular volume fraction 3. Capillary permeability 4. Relationship between glycaemic markers and LV perfusion parameters 5. Aortic distensibility Secondary outcome measures will be measured by cardiac MRI at baseline and at weeks 12 and 24. Secondary outcome measure 4 will also be measured at approximately 2 weeks before baseline and at weeks 10 and 22. |
| Overall study start date | 16/04/2018 |
| Completion date | 30/06/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 84 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 60; UK Sample Size: 60 |
| Total final enrolment | 36 |
| Key inclusion criteria | 1. Type 2 diabetes mellitus 2. Metformin as single or dual therapy 3. Recent heart attack (<12 months) 4. HbA1c >48mmol/ml 5. 18-84 years old 6. Ability to provide informed consent |
| Key exclusion criteria | 1. Previous coronary artery bypass grafting (CABG) 2. Need for further revascularisation 3. Contra-indication to CMR scanning (some pacemakers, intraorbital debris, intraauricular implants, intracranial clips etc) 4. Contra-indication to Adenosine 5. Known allergy to contrast medium (gadolinium) 6. Renal dysfunction with eGFR< 60 7. Obesity where girth exceeds the scanner bore 8. Pregnancy or breastfeeding 9. Inability to lie flat for CMR scan |
| Date of first enrolment | 29/08/2018 |
| Date of final enrolment | 03/01/2022 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Leeds
LS1 3EX
United Kingdom
Sponsor information
University/education
Faculty Research Office
Room 9.29 Level 9 Worsley Building
Clarendon Way
Leeds
LS2 9NL
England
United Kingdom
| Phone | +44 (0)113 3437587 |
|---|---|
| governance-ethics@leeds.ac.uk | |
"ROR" |
https://ror.org/024mrxd33 |
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- the_bhf, The British Heart Foundation, BHF
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v1.2 | 19/06/2018 | 16/10/2018 | No | Yes |
| Participant information sheet | version v1.3 | 17/01/2019 | 06/09/2019 | No | Yes |
| Protocol file | version v1.2 | 17/01/2019 | 06/09/2019 | No | No |
| Protocol article | 01/05/2021 | 13/08/2021 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN82391603_PIS_v1.2_19Jun18.docx
- Uploaded 16/10/2018
- ISRCTN82391603_PIS_v1.3_17Jan2019.pdf
- Uploaded 06/09/2019
- ISRCTN82391603_Protocol_v1.2_17Jan2019.pdf
- Uploaded 06/09/2019
Editorial Notes
25/08/2022: The following changes were made to the trial record:
1. The intention to publish date was changed from 30/06/2023 to 31/12/2022.
2. A contact was removed.
25/08/2022: The following changes were made to the trial record:
1. Total final enrolment added.
2. The recruitment end date was changed from 01/06/2020 to 03/01/2022.
3. The overall trial end date was changed from 31/12/2020 to 30/06/2022.
4. The intention to publish date was changed from 31/12/2021 to 30/06/2023.
13/08/2021: Internal review.
30/06/2021: Publication reference added.
23/04/2020: Due to current public health guidance, recruitment for this study has been paused.
06/09/2019: The following changes have been made:
1. The contacts' ORCIDs have been added.
2. The IRAS number has been added.
3. The acronym has been added.
4. Uploaded protocol Version 1.2 17 Jan 2019 (not peer reviewed).
5. An updated participant information sheet has been uploaded.
04/09/2019: Dr Kathryn Richards has been added as an additional scientific contact.
03/09/2019: The scientific contact has been updated.
25/03/2019: The condition has been changed from "Specialty: Cardiovascular Disease, Primary sub-specialty: Atherothrombosis; Health Category: Cardiovascular; Disease/Condition: Ischaemic heart diseases, Diabetes mellitus" to "Heart disease in patients with type 2 diabetes and previous myocardial infarction" following a request from the NIHR.
16/10/2018: The participant information sheet has been uploaded.
