Clinical trial NCT02397421: Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes
Official title: Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Diabetes
Keywords: Heart failure
Diabetes
Left ventricular remodelling
SGLT-2 inhibitors
Lead sponsor: University of Dundee
Sponsor class: OTHER
Collaborators: name: European Foundation for the Study of Diabetes
First posted: 2015-03-25
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with diabetes are at increased risk of developing heart failure (HF) which can lead to increased shortness of breath, reduced ability to exercise and in some cases premature death as the heart becomes less efficient at pumping blood around the body. However the treatment options for such patients remain limited.

This study will test the safety and benefits of using a new class of drug, the SGLT2 Inhibitor (Dapagliflozin), in treating HF and diabetes.

Participants will have a Magnetic Resonance Imaging (MRI) scan of the heart, to measure the efficiency and the extent of thickening of the heart muscle before they start on treatment of dapagliflozin, or placebo for one year. They will also do exercise testing on an exercise bike (if capable) and a walking test plus fill in some questionnaires on how their heart failure affects their quality of life. Participants will then continue as normal with currently prescribed medication for their diabetes and heart failure. After a year the tests will be repeated to determine if patients receiving Dapagliflozin benefited more than those who weren't on the drug.

This study is funded by the European Foundation for the Study of Diabetes (EFSD)

Detailed description: Men and women with diabetes have a 2-5-fold increased risk of heart failure (HF). The prevalence and incidence of HF is increasing in diabetes and mortality rates remain alarmingly high. This highlights the need for novel therapies in diabetes that will reduce HF risk and /or delay disease progression.

Drug options are currently limited as some diabetic therapies such as thiazolidinediones are contra-indicated in HF. SGLT2 inhibitors, the newest class of anti-diabetic drugs, are an exciting new approach to diabetes management that may have additional beneficial effects in diabetes and HF. SGLT2 inhibitors may have beneficial effects on adverse left ventricular (LV) remodelling that occurs in patients with diabetes and heart failure by reducing the load on the heart through its diuretic and blood pressure lowering actions.

Exercise intolerance is a cardinal symptom of patients with HF and improving insulin sensitivity has been shown to improve exercise capacity. SGLT2 inhibition has been shown to improve insulin sensitivity and to reduce weight and therefore has the potential to improve exercise capacity in HF.

This study will assess the potential beneficial effects of the oral SGLT2 inhibitor, dapagliflozin, on LV remodelling and exercise capacity in patients with diabetes and HF. The findings of this study may help to establish the utility of SGLT2 inhibitors in diabetic patients with HF and provide important clinical data on the impact of SGLT2 inhibition on LV remodelling.

Eligibility criteria: Inclusion Criteria:

* were previously diagnosed with Type 2 Diabetes
* are diagnosed with NYHA functional class I-III HF with prior echocardiographic evidence of Left Ventricular Systolic Dysfunction (LVSD) (At least mild LV systolic dysfunction on sonographer assessment or ejection fraction at 45% or less)
* on furosemide 80mg daily or less, or equivalent loop diuretic
* have stable HF symptoms for at least three months prior to consent
* on stable therapy for HF for at least three months prior to consent
* have not been hospitalised for HF for at least three months prior to consent

Exclusion Criteria:

* severe hepatic disease
* renal disease defined as Chronic Kidney Disease (CKD) class 3b or worse (i.e. estimated glomerular filtration rate (eGFR) / creatinine clearance CrCl \<45ml/min)
* systolic BP \<95mmHg at screening visit
* screening HbA1c \<6.0%
* unable to walk to perform cardio pulmonary exercise testing or 6MWT
* malignancy (receiving active treatment) or other life threatening diseases
* pregnant or lactating women
* any contraindication to MRI (e.g. claustrophobia, metal implants, penetrative eye injury or exposure to metal fragments in eye requiring medical attention)
* patients who have participated in any other clinical trial of an investigational medicinal product within the previous 30 days
* patients who are unable to give informed consent
* any other reason considered by a study physician to be inappropriate for inclusion.

Primary outcomes:
measure: Change in LV end systolic volume (absolute value and indexed for BSA) or LV end diastolic volume (absolute value and indexed for BSA)
timeFrame: 1 year
Secondary outcomes:
measure: Change in LV mass, LV ejection fraction, RV end diastolic volume, RV end systolic volume, RV ejection fraction, atrial dimensions and volumes, and LV remodelling index (LV mass / LVEDV)
timeFrame: 1 year
measure: Fluid status (Bioelectrical Impedence Analysis (BIA)
timeFrame: 1 year
measure: Objective functional capacity (6 Minute Walk Test (6MWT)
timeFrame: 1 year
measure: Exercise capacity (Cardio-pulmonary Exercise Testing (CPET)
timeFrame: 1 year
measure: Quality of life (Minnesota Living with Heart Failure and SF-36 questionnaire)
timeFrame: 1 year
measure: Cardiac and inflammatory biomarkers
timeFrame: 1 year
measure: Diuretic requirement (total diuretic requirement to maintain euvolemia)
timeFrame: 1 year
measure: Change in degree of microalbuminuria
timeFrame: 1 year
measure: Quantify amount of natriuresis
timeFrame: 1 year
measure: The safety of dapagliflozin use in diabetic, heart failure patients with regard to worsening HF, hospitalization and death will be evaluated
timeFrame: 1 year
Other outcomes:
Locations:
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
state: Angus
Study officials:
affiliation: University of Dundee
name: Jagdeep Singh, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.
citation: Singh JSS, Mordi IR, Vickneson K, Fathi A, Donnan PT, Mohan M, Choy AMJ, Gandy S, George J, Khan F, Pearson ER, Houston JG, Struthers AD, Lang CC. Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial. Diabetes Care. 2020 Jun;43(6):1356-1359. doi: 10.2337/dc19-2187. Epub 2020 Apr 3.
citation: Singh JS, Fathi A, Vickneson K, Mordi I, Mohan M, Houston JG, Pearson ER, Struthers AD, Lang CC. Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Cardiovasc Diabetol. 2016 Jul 15;15:97. doi: 10.1186/s12933-016-0419-0.