Consensus statement issued regarding TZDs and CHF

Amid concerns of a link between thiazolidinedione (TZD) use and congestive heart failure (CHF), the American Heart Association and the American Diabetes Association have issued a joint consensus statement to guide physicians on the use of TZDs in patients who may have underlying heart disease (Circulation 2003;108[23]:2941-2948).

After diet, exercise, and single-drug therapy in patients with type 2 diabetes, TZDs are indicated to help achieve target glucose levels. These agents may also improve other cardiovascular disease variables, such as lipids, blood pressure, and inflammatory markers. Thus, they are widely used among patients with type 2 diabetes, a population with a high risk for cardiovascular disease.

Reports noting edema and possibly consequent CHF have raised concerns that TZDs may have an additive effect in the development of CHF. “It is sometimes difficult to know whether such swelling is a benign side effect of the drugs or a more ominous sign of heart failure,” said Richard Nesto, MD, lead author of the joint statement and chair, department of cardiovascular medicine, Lahey Clinic, Burlington, Massachusetts. Diabetes itself is a strong, independent risk factor for CHF.

The workgroup evaluated the use of TZDs in patients with heart disease and in those who developed edema or weight gain in the course of therapy with a TZD. The panel reviewed studies examining TZDs and found they cause weight gain, which is more dramatic when the drug is added to insulin therapy. The weight gain seems to be dose-dependent and a function of improved glycemic control and fluid retention. There is an increased incidence of edema with the use of TZDs, especially when used with other glucose-lowering agents, most notably insulin. But the report notes that patients with type 2 diabetes who are taking insulin are likely to be older, have hypertension, left ventricular hypertrophy, and coronary heart disease, all of which contribute to edema.

An examination of studies of CHF in patients treated with TZDs reveals that its incidence is low, but is definitely higher in patients treated with insulin as well as in those treated with high-dose TZDs or who have other risk factors for CHF. The report suggests that an increase in plasma volume is the likely culprit in the pathogenesis of CHF with TZD use.

In case reports describing the occurrence of CHF in patients treated with TZDs, CHF occurred in patients with depressed or normal systolic function, usually when the TZD was used with insulin. Clinicians are cautioned to be aware that significant CHF may be directly attributable to TZD therapy and may occur in patients who seem to be at low risk.

In light of these findings, the workgroup made detailed recommendations in the consideration of TZD therapy. Before prescribing a TZD, clinicians should:

• ascertain whether a patient has underlying cardiac disease, including myocardial infarction (MI), coronary heart disease, CHF, or valve disease.

• note whether a patient is taking drugs that may cause fluid retention or edema.

• determine whether the patient has shortness of breath, and monitor closely for this sign during the first several months of TZD treatment.

• review the electrocardiogram for silent MI or left ventricular hypertrophy.

• instruct the patient to report a gain of more than 3 kg, pedal edema, shortness of breath, or excessive fatigue.

Patients without heart disease. Clinicians should expect that weight gain and edema will occur more often in patients taking insulin therapy. In patients with one or more risk factors for CHF, the dosage of a TZD should be started low and increased gradually while monitoring for excessive weight gain, edema, or CHF.

The statement defines risk factors for CHF as a history of CHF, previous MI or coronary heart disease, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age older than 70 years, long-standing diabetes of more than 10 years, edema or treatment with loop diuretics, development of edema or weight gain during TZD therapy, insulin coadministration, and chronic renal failure. For patients with a depressed ejection fraction, the TZD should be started at a low dosage and increased gradually, because patients with depressed cardiac function are at higher risk of CHF due to fluid retention.

Patients with heart disease. In patients with symptomatic heart disease, this class of drugs should be used cautiously in patients with New York Heart Association (NYHA) functional class I or II heart failure, with initiation of treatment at a lower dosage. Patients should be monitored closely for weight gain, edema, or exacerbation of CHF as the dosage is increased. TZDs should not be used in patients with signs or symptoms of NYHA class III or IV heart failure.

If edema develops in the first few months of TZD treatment, clinicians should carefully observe for symptoms and signs of CHF, such as orthopnea, paroxysmal nocturnal dyspnea, unexplained cough or fatigue, pedal edema, jugular venous distention, an S3 gallop, and pulmonary rales. Such symptoms and signs may indicate CHF despite absence of a history of heart disease, and are cause for performing tests of cardiac function. When edema occurs without evidence of CHF, other causes should be ruled out, including the use of drugs associated with pedal edema, venous insufficiency, or nephritic syndrome.

If a new diagnosis of CHF is made in the absence of dysfunction, the dosage of the TZD should be changed or its use reconsidered. For patients with known left ventricular dysfunction, TZDs should be discontinued.