Do diuretics do more harm than good?

Metformin and TZDs

Diabetes and heart failure are not a healthy combination. "Patients with diabetes do have worsening long-term outcomes," said W. H. Wilson Tang, M.D., assistant professor of medicine at Cleveland Clinic Lerner College of Medicine.

TZDs are approved for use only in early heart failure. Increased risk of edema has been the main concern, said Tang. In clinical studies, despite edema and weight gain, heart failure mortality did not differ. Both TZDs now on the market-pioglitazone (Actos, Takeda), and rosiglitazone (Avandia, GlaxoSmithKline)-have shown a wide range of heart benefits, Tang said. Whether biguanides and TZDs are safe and effective in heart failure patients remains to be seen, but "risk concerns for metformin and the TZDs have not translated into increased mortality risks," Tang said.

Targeting insulin resistance

Insulin resistance plays a key role in heart failure. "In the absence of other risk factors, heart failure itself is associated with whole body and heart insulin resistance," said Richard P. Shannon, M.D., chairman, department of medicine, Allegheny General Hospital, Pittsburgh. He has been researching the mechanism of insulin resistance in cardiac muscle. He believes cardiac insulin resistance may be due to decreased mitochondrial function and decreased oxidation. There is glucose present for cardiac muscle to consume, but it is unable to do so; the heart is starving in the presence of plenty. A series of peptides called glucagon-like peptides (GLPs) may offer a remedy. He has studied one-GLP-1-to see if it would reverse cardiac insulin resistance.

In the clinical study, a subcutaneous infusion of GLP-1 for 10 weeks yielded a clinical benefit. The drug was insulinomimetic and was associated with minimal risk of hypoglycemia. GLP-1 suppressed glucagons, increased contractility, and increased glucose uptake without changing plasma insulin.

Preserving renal function

"Renal dysfunction is common in patients with acute decompensated heart failure," said Michael M. Givertz, M.D., codirector of the cardiomyopathy and heart failure program at Brigham & Women's Hospital, Boston. "And the problem is worse than we thought."

Current diuretics do not always reduce edema, and some may cause more harm than good. "Loop diuretics appear safe in the short term but activate RAAS in the longer term," said Mark C. P. Haigney, M.D., an electrophysiologist in the division of cardiology at Uniformed Services University of the Health Sciences in Bethesda, Md. The renin-angiotensin-aldosterone system (RAAS) regulates blood volume and pressure. Haigney's animal study found that furosemide decreased survival by 40% when used during heart failure.

Adenosine antagonists may be a novel approach to diuresis and can improve renal function and blood flow, Givertz said. Ongoing studies are evaluating safety and efficacy in this new class of drugs.