Efficacy of Metformin as add-on Therapy in Non-Diabetic Heart Failure Patients

There is an increasing interest in the use of metformin in CV diseases and there is an increasing interest in studying its potential new roles in heart failure patients. There were some concerns related to the safety of metformin in such diabetic patients due to the risk of lactic acidosis. However, recent studies showed that metformin was safe or even beneficial in HF patients. We hypothesized that metformin might improve morbidity, mortality, cardiac function, and HR-QoL in non-diabetic patients with HFrEF.

Metformin is an anti-diabetic drug that is known improve insulin sensitivity and reduce insulin resistance. A published meta-analysis of randomized controlled trials (RCTs) reported a reduction of weight and insulin resistance in metformin users. Animal models also showed that metformin reduces cardiac hypertrophy. Observational studies showed a beneficial effect for metformin in patients with type 2 diabetes mellitus (T2DM) and heart failure. A recent study found that metformin reduced oxidative stress in non-diabetic patients with CAD.

Metformin has multiple modes of actions involving both AMP-activated protein kinase (AMPK) dependent and AMPK-independent mechanisms that may be implicated in cardiac hypertrophy. At the systemic level, a review of clinical and experimental data showed that metformin improves endothelial function, protects from oxidative stress and inflammation, as well as the negative effects of angiotensin II. Observational studies also reported cardiovascular benefits in metformin users especially in patients with type 2 diabetes mellitus (T2DM) and heart failure. Metformin has also been shown to exert a cardio protective effect and it has been shown to reduce oxidative stress which is a common finding in heart failure patients. For these reasons, there is an increasing interest in the use of metformin in CV diseases and there is an increasing interest in studying its potential new roles in this aspect. We hypothesized that metformin might improve morbidity, mortality, cardiac function, and HR-QoL in non-diabetic patients with HFrEF.

Eligibility Criteria:
Inclusion Criteria:

* Chronic heart failure (\>6 months duration)
* Stabilized on recommended or maximally tolerated dose of ACE-I/ARB or ARNI (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated).
* Reduced ejection fraction defined as LVEF \< 45%
* NYHA-class II or III or IV with stable symptoms for at least the past 3 months
* Creatinine clearance \> 45 ml/min

Exclusion Criteria:

* Diabetes mellitus: Diabetes will be diagnosed using the 2018 The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes 15

  * FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.\*
  * 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.
  * A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.\*
  * In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).
* Any oral or injectable hypoglycemic therapy (e.g. insulin, sulfonylureas)
* Recent Hospitalizations in the past 3 months
* Metformin treatment within the last 3 months
* Creatinine clearance below 45 in the prior 6 months as assessed by Cockcroft and Gault equation
* Known allergy to metformin or major side effects to metformin treatment
* Atrial fibrillation with poorly controlled ventricular rate at rest (\> 100 beats/min)
* Hypertrophic cardiomyopathy