Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design

Abstract

BackgroundHeart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively.MethodsThe REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others.ConclusionsThis trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF.Trial registration Clinical Trials.gov: NCT02397421. Registered 12th March 2015

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

“…31 Other RCTs investigating the effects of SGLT2i on LV remodelling in patients with T2D and HF are currently ongoing. 32,33 A RCT exploring cardiac effects of SGLT2i using impedance cardiography showed that 12 weeks of treatment with dapagliflozin had no significant effects on cardiodynamic parameters related to blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content), compared to placebo. 34 Several possible mechanisms have been suggested to explain the beneficial effect of SGLT2i on cardiovascular outcomes, but not yet formally proven.…”

The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions

“…Further larger studies utilizing novel cardiac imaging modalities to more precisely quantify cardiac structure and function, particularly indicators of early LV dysfunction, would be of great benefit. There are currently ongoing clinical studies that are also utilizing cardiac magnetic resonance imaging to assess the effects of SGLT2 inhibitors on cardiac structure and function, as shown in Table . In addition, studies utilizing speckle‐tracking echocardiography for the measurement of global longitudinal strain and three‐dimensional echocardiography for more accurate quantification of LV structure in people with diabetes and normal LV ejection fraction are underway .…”

The Effect of Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibitors on Cardiometabolic Profile; Beyond the Hypoglycaemic Action

“…Data from an experimental study reported empagliflozin treatment in diabetic and hypertensive rats, resulted in reductions in adverse LV remodelling, as suggested by changes in LV mass, and LV dilatation, while increased cardiac contractility [ 83 ]. The REFORM trial a, phase IV, RCT, aims to shed further by examining the effect of dapagliflozin on LV parameters in patients with known heart failure [ 84 ]. In the meantime, the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) study is examining the effect of SGLT2 inhibition on CV events in patients without pre-existing macrovascular disease (i.e.…”