Diabetes Mellitus, Type 2, Diabetes Mellitus Type 2 in Obese, Heart Failure, Diastolic, Heart Failure With Preserved Ejection Fraction, Obesity Adult Onset
Conditions
Keywords
Heart failure with preserved ejection fraction, Diastolic heart failure, Type 2 diabetes mellitus, Obesity, Meal replacement plan, Cardiac magnetic resonance imaging, Exercise intolerance, Diabetes remission
Brief summary
Heart failure with preserved ejection fraction (HFpEF) is a common and serious complication of obesity and type 2 diabetes (T2D). HFpEF occurs when the heart muscle unable to relax efficiently to pump the blood around the body. This leads to fluid build-up, breathlessness and inability to tolerate physical exertion. People who develop HFpEF do less well because treatment options are limited. Pilot data in patients with obesity and diabetes and a small number of patients with HFpEF have shown improvements in exercise capacity and reversal of changes in the heart and blood vessels. This study will assess if this is achievable in a multi-ethnic cohort of patients with established HFpEF. A total of 63 adults will be invited and allocate by chance into two groups: 1) 12-weeks of a low calorie diet or 2) Standard care and health advice on how to lose weight followed by the option to have the low calorie diet after 12-weeks. The study will determine if weight loss over 12 weeks can improve heart function, symptoms and ability to exercise. Additionally, participants' views on changing their diet and how this has impacted their symptoms will be sought during the study in an optional interview. This will help guide treatments planning in the future to get maximum benefits, and to individualize support to patients from different cultural backgrounds.
Detailed description
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogenous syndrome, typified by severe exercise intolerance and with limited treatment options. Weight loss achieved through a low energy meal-replacement plan (MRP) has been shown to lead to reversal of cardiovascular remodelling in ethnically diverse asymptomatic adults with pre-HFpEF and HFpEF. This trial will translate this experience with the pragmatic low energy MRP into a symptomatic, multi-ethnic cohort of obese HFpEF, across four sites (Leicester, Manchester, Leeds and Oxford) to assess its efficacy in improving exercise intolerance, symptoms, quality of life, cardiovascular remodelling, and skeletal myopathy.
Interventions
Meal replacement diet containing \~850 kcal/day (40% protein, 50% carbohydrate, 10% fat) supplied by Counterweight® (www.counterweight.org).The meal replacement plan will comprise of 3-4 meal packs/day (to equate to 850 kcal) with sweet and savoury options, and an allowance of 100ml semi-skimmed milk or a non-dairy alternative.
CMR scanning performed on a 3T MRI scanner. Standardised protocol incorporating cine functional assessment to determine LV mass, systolic function and left atrial volumes; global systolic strain and diastolic strain rates will be assessed by tagging and with tissue tracking analysis from cine images, adenosine rest and stress myocardial perfusion to assess reserve index and qualitative perfusion defects, aortic distensibility to measure aortic stiffness, delayed contrast enhancement for assessment of LV fibrosis and evidence of previous myocardial infarction. Myocardial and liver triglyceride content will be assessed using the modified Hepafat® sequence or 1H MR spectroscopy at the inter ventricular septum. Additional imaging will be undertaken for quantification of visceral adiposity and subcutaneous adipose tissue. Cardiac 31P magnetic resonance spectroscopy imaging to assess cardiac muscle energetics according to a standardised operating procedure.
DIAGNOSTIC_TESTTransthoracic echocardiography
Comprehensive transthoracic echocardiography, including: tissue Doppler indices of diastolic filling, exclusion of valvular abnormalities, assessment of LV size and function
DIAGNOSTIC_TESTBlood test
Collection of blood samples from each participant to characterise the participant's health status and fibroinflammatory markers.
DIAGNOSTIC_TESTElectrocardiogram
An ECG will be obtained to assess for baseline rhythm.
DIAGNOSTIC_TESTAccelerometery
Accelerometer (GeneActiv) measured daily activity levels continuously for 7 consecutive days.
DIAGNOSTIC_TEST6 minute walk test (6MWT)
Supervised 6MWT will be performed with symptom assessment using dyspnoea scale (Borg's).
DIAGNOSTIC_TESTSkeletal muscle strength using handgrip strength
Skeletal muscle strength will be measured using hand grip strength
OTHERAssessment of quality of life and heart failure symptoms
Quality of life and HF symptoms will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) questionnaire, which is used as a standardised measure of self-reported health status, and HF symptoms and is considered to have a good discriminatory power and validity
OTHERAssessment of sarcopenia
Participants will be assessed for presence of sarcopenia using the Strength, Assistance with walking, Rise from a chair, Climb stairs and Falls (SARC-F) questionnaire. It is a robust tool for diagnosis of sarcopenia and prediction poor physical function, with excellent specificity in multimorbid individuals.
Frailty will be assessed using the Edmonton Frail Scale (EFS). The EFS is a multidimensional frailty assessment which assesses multiple domains of frailty including functional independence, social support, cognition, medication use, and mood.
OTHERQualitative interview
Participants in the MRP and control groups will be invited to attend a focused semi-structured, 1-2-1 interview aimed to elicit barriers and enablers to the MRP and describe their perspective on the relationship between healthy eating and health interview during the 12-week visit. Participants who complete or drop out will be eligible. Inclusion of participants in the control arm will allow us to compare the experiences of MRP versus health coaching and detect any specific issues people face when trying to introduce lifestyle changes themselves.
Sponsors
University of Leicester
University of Oxford
University of Manchester
University of Leeds
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Participants and investigator will not be blinded to treatment allocation (open label) however, the team analysing the outcomes, where possible, will be blinded to treatment allocation.
Intervention model description
Multi-centre, prospective, open-label blinded end-point randomised wait-list controlled trial of low-energy Meal Replacement Plan (MRP) versus guideline-driven care, and a nested qualitative sub-study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Established clinical diagnosis of heart failure with preserved ejection fraction HFpEF (EF\>45%) made by a cardiologist or a primary care physician with heart failure expertise, or a heart failure nurse 2. Clinically stable for ≥ 3 months (no admissions to hospital) 3. Obesity (BMI ≥30kg/m2 if white European or ≥27kg/m2 if Asian, Middle Eastern or Black ethnicity) 4. Age ≥18
Exclusion criteria
1. Inability to walk/undertake 6-minute walk test 2. Inability to follow a low-energy MRP 3. HFpEF due to infiltrative cardiomyopathy (cardiac amyloidosis or sarcoidosis), genetic hypertrophic cardiomyopathy, restrictive cardiomyopathy/pericardial disease or congenital heart disease. 4. Recovered EF (previous EF \< 40%) unless reduced EF was in context of tachycardia induced cardiomyopathy (eg AF/Aflutter). 5. Known heritable, idiopathic or drug-induced pulmonary arterial hypertension 6. Severe chronic obstructive pulmonary disease (FEV1\< 1.0L) 7. Severe primary valvular heart disease 8. Anaemia (Hb\<100g/L) 9. Severe renal disease (eGFR \< 30 ml/min/1.73 m2) 10. Weight loss \> 5kg in preceding 3 months. 11. Symptomatic gallstones (including biliary colic) or cholecystitis within last 3 months 12. Active substance abuse (drugs or alcohol) 13. History of bariatric surgery in the last 3 years 14. Active illness likely to cause change in weight 15. Women who are pregnant or are considering pregnancy 16. People currently participating in another clinical research trial that is likely to affect diet or weight change. 17. History of a severe mental illness including an eating disorder 17\. Individuals with a diagnosis of Type 1 diabetes mellitus.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the distance walked during 6 minute walk test (6MWT) | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | The primary outcome measure is a change in the distance walked on 6MWT measured in meters |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Beneficial reverse cardiovascular remodelling | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | CMR-derived measures of cardiovascular remodelling defined as left ventricular mass/volume ratio |
| Change in physical activity levels | Assessed at baseline and 12 weeks | Improvement in physical activity will be determined by change in daily activity as determined accelerometery |
| Change in upper limb muscle power | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | Change in muscle power will be determined by handgrip strength |
| Improvement in exercise tolerance | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | This will be assessed by change in Borg dyspnoea scale during 6MWT |
| Improvement in symptoms of heart failure | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | This will be assessed by a change in the Kansas City Cardiomyopathy Questionnaire score |
| Change in sarcopenia | Assessed at baseline and 12 weeks, optional repeat at 24 weeks | This will be assessed by a change in the SARC-F questionnaire score |
| Exploratory outcome: Improving skeletal and cardiac energetics | Baseline and 12 weeks | 31P magnetic resonance spectroscopy: Cardiac PCr/ATP |
| Exploratory outcome: change in fibroinflammatory biomarker panel | This will be evaluated at baseline and at 12 weeks | Exploratory analysis of the fibroinflammatory biomarker panel to identify potential pathways involved in the development, progression or outcomes of HFpEF. |
Countries
United Kingdom
Contacts
CONTACTSarah L Ayton, MBBS
CONTACTEmer M Brady, PhD
PRINCIPAL_INVESTIGATORGerry P McCann, MD
University of Leicester
Outcome results
None listed