Management of Diabetes With Metformin In Patients With Chronic Heart Failure

Heart failure (HF) affects 5 million individuals in the United States including over 10% of elderly persons >75 years. HF mortality is high, with approximately 20% 1-year risk of death (1). Diabetes (DM) is a common co-morbidity in patients with HF, present in approximately 25% of stable outpatients and 40% of hospitalized patients with HF (2). Diabetes in HF patients is associated with higher mortality (3,4). Hyperglycemia is independently associated with hospitalization for HF, longer length of stay during HF hospitalization, as well as higher in-hospital HF mortality (5-7). Furthermore, HF patients with more symptoms and worse functional status are more likely to have insulin resistance (8,9).

Despite the abundance of evidence linking diabetes, insulin resistance, and hyperglycemia to impaired functional status and worse outcomes in patients with HF, there is lack of data and guidelines on optimal strategies to manage diabetes in patients with chronic HF. In retrospective studies, many diabetes medications in HF have been associated with harm including insulin, thiazolidinediones, and sulfonylureas (10). The only anti-hyperglycemic medication that has been associated in retrospective studies with benefit in patients with HF and diabetes is metformin, which recently had its "black box warning" in HF lifted by the FDA, although most physicians are unaware of the change in labeling (10-12). Our analysis of data on 401 advanced, systolic HF patients with DM followed at the Ahmanson-UCLA Cardiomyopathy Center also found metformin therapy to be associated with improvement of left ventricular ejection fraction (LVEF) as well as decreased 1-year mortality (figure 1)(13).

Glycemic control in HF patients has not been prospectively studied; however, improved glycemic control has potential benefits in HF, including improvement of myocardial glucose utilization, decrease of potentially cardiotoxic free fatty acids, and reduced accumulation of myocardial collagen and advanced glycation end-products (14,15). Metformin therapy, compared to insulin and other antidiabetic medications, has potentially beneficial mechanisms of action in HF including insulin sensitization, improvement in lipid profiles, and more efficient myocardial metabolism (16,17). The purpose of this study is to gather pilot data for an anticipated comprehensive study DM management in HF, with the goal of NIH funding.

Inclusion criteria

• Systolic HF of any etiology (left ventricular ejection fraction ≤ 40%)
• Previously-diagnosed, inadequately controlled DM (HbA1c≥7.5%)
• On any combination of anti-diabetic medications excluding metformin

Exclusion criteria

• Current metformin therapy
• Previous intolerance to metformin therapy
• Renal dysfunction (creatinine clearance < 60 ml/minute)
• History of lactic acidosis.