Purpose:

The overall hypothesis of the study is that the benefits attained in the EMPA-OUTCOME were, at least in part, mediated by a glucose-independent mechanism. Thus, to demonstrate the existence of the postulated non-glucose dependent effects, the researchers will investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in heart failure patients with reduced ejection fraction without diabetes.

Heart failure (HF) is a frequent co-morbid condition associated with poor prognosis in diabetes, particularly among older patients. HF accounts for more than 1 Million hospitalizations annually in USA. In addition, HF hospitalizations are associated with significant high risk of post-discharge mortality and recurrent hospitalizations. Almost one-half of patients will be re-hospitalized within 6 months and one-third will die within 12 months of discharge. Median survival after HF diagnosis is about 5 years and is similar for HFpEF and heart failure with reduced ejection fraction (HFrEF) patients. Diabetes as co-morbidity multiplies risk of hospital admissions in HF patients.

Type 2 Diabetes Mellitus (T2DM) is a pathological condition characterized by elevated glucose levels and it is associated with high incidence of cardiovascular (CV) events. Several hypoglycemic agents have successfully managed the elevated glucose levels but with little or no impact on CV events. Management of concomitant HF in T2DM is particularly challenging, as some glucose-lowering agents, such as TZDs, are contraindicated in the treatment of HF patients. Thus, there was a need for an oral agent that improved glycemia as well as provided CV benefits. Empagliflozin is the first glucose-lowering agent showing that not only improves glycemic control but also has cardiovascular benefits. The recent EMPA-OUTCOME trial has shown significant reductions in major adverse cardiac events (MACE), cardiovascular mortality, and hospitalization for Heart Failure (HF) by Empagliflozin given on top of standard-of-care therapy for T2DM patients with Cardiovascular disease (CVD). The dramatic change driving the superiority of the primary composite outcome was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35% and 38% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively.

Empagliflozin is a member of a new class of hypoglycemic agents, the SGLT-2 inhibitors. There are a couple of characteristics that single out the SGLT2 inhibitors from other hypoglycemic drugs. One is their low hypoglycemic risk since they act on the urinary excretion of glucose without interfering with the physiologic response to hypoglycemia. And the other is their "positive" cardiovascular effects such as lowering blood pressure, arterial stiffness, urinary microalbuminuria and triglycerides while increasing HDL-Cholesterol levels. Therefore, the combination of the above-mentioned observations led to some investigators to suggest that these benefits may be, at least in part, independent of its hypoglycemic activity and thus, Empagliflozin could be considered a "cardiac" drug.

Inclusion Criteria:

• Patients should meet the following inclusion criteria:
• Ambulatory patients age 18-85 years
• Diagnosis of Heart failure (NYHA II to III)
• LVEF<50% on echocardiography or CMRI in the previous 6 months
• Have stable symptoms and therapy for HF within the last 3 months.

Exclusion Criteria:

• Pregnant or lactating women.
• Any history of diabetes by medical history or by any of the established criteria by the American Diabetes Association. It also includes patients with history of diabetes in remission.
• ACS or cardiac surgery within the last 3 months.
• Cancer or any other life-threatening condition.
• Pancreatitis.
• Glomerular Filtration Rate < 45 ml/Kg/min.
• Use of continuous parental inotropic agents.
• Systolic BP < 90 mm Hg.
• Psychiatric disease incompatible with being in study.
• Any contraindication to MRI procedures.
• Any other medical or physical condition considered to be inappropriate by a study physician.

6 months

This is a single-site trial with a relatively small number of patients; however, the high reproducibility of CMR allows for the utilization of reduced sample sizes. A second limitation is the relatively high number of dropouts in the CPET. Third, this trial have exclusively studied heart failure with reduced ejection fraction(HFrEF) patients; whether patients with heart failure with preserved ejection fraction can benefit from SGLT2i cannot be answered by this study and remains to be determined.