Thiazolidinediones Contraindicated in Patients at Risk for Heart Failure CME
News Author: Laurie Barclay, MD CME Author: Charles Vega, MD Authors and Disclosures
Dec. 8, 2003 - A joint statement from the American Heart Association (AHA) and the American Diabetes
Association (ADA), published in the Dec. 9 issue of Circulation, urges physicians not to prescribe
thiazolidinediones (TZDs) to patients at risk for congestive heart failure (CHF). The statement will
also be published in the January 2004 issue of Diabetes Care.
"There is now widespread use of TZDs in a broad group of patients with type 2 diabetes," lead author
Richard W. Nesto, MD, from the Lahey Clinic in Burlington, Massachusetts, says in a news release.
"At the same time there have been reports of CHF associated with their use."
The TZDs rosiglitazone maleate (Avandia) and pioglitazone hydrochloride (Actos) are indicated as
monotherapy or as combination therapy for type 2 diabetes. Although these drugs help control blood
glucose and may improve other cardiovascular risk factors including hypertension, high cholesterol,
and inflammatory biomarkers, some patients treated with these drugs develop edema.
"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," Dr. Nesto says. "It is this common association that concerns
both cardiologists and diabetologists."
To balance improved glycemic control achieved with TZDs against potential risk, the joint statement
writing committee reviewed existing trials to identify diabetic patients who are at increased risk
for CHF and who may not be ideal candidates for TZDs.
Recommendations of the consensus statement include avoidance of TZDs in patients with advanced heart
disease or severe CHF. In patients with depressed ejection fraction but without symptoms of CHF,
TZDs should be prescribed only if glycemic control cannot be achieved with other drugs, and in these
cases TZDs should be started at low doses.
The statement also recommends a "start low, go slow" regimen of TZDs for diabetics with mild to
moderate CHF, and in those with one or more risk factors for CHF. Because diabetes is a
cardiovascular risk factor, many patients given TZDs for diabetes could also have underlying
heart disease.
"But at this point we don't know the real risk because we don't know either the actual number of
patients with diabetes who are taking a TZD and develop CHF, compared to the total number of
patients who are taking a TZD," Dr. Nesto says. "This risk is probably quite low, but without solid
data that's just guesswork."
According to the statement, patients receiving TZD treatment should report weight gain of more than
3 kg (6.6 lb), sudden onset of pedal edema, dyspnea, or fatigue. For CHF diagnosed after initiation
of TZD therapy, "dosage change and temporary or permanent discontinuance are the obvious options,
but no one of these is preferred for all patients," the authors write.
Circulation. 2003;108:2941-2948
Learning Objectives Upon completion of this activity, participants will be able to: List the
nonhypoglycemic benefits of TZDs. Describe how TZDs should and should not be used in the presence of
CHF and CHF risk factors. Clinical Context TZDs have emerged as a treatment option for patients with
diabetes in part due to effects beyond their ability to lower serum glucose. In a review by Parulkar
and colleagues appearing in the Jan. 2, 2001, issue of the Annals of Internal Medicine, the authors
cite reduced blood pressure, correction of diabetic dyslipidemia, improvement in fibrinolysis, and a
decrease in carotid artery intima-media thickness as other benefits associated with TZDs. However,
the authors tempered their enthusiasm for TZDs in a discussion of the weight gain associated with
the drugs.
Weight gain and fluid retention are known adverse events associated with TZD use. In a retrospective
analysis by Tang and colleagues of diabetic patients with known heart failure using TZDs, 17.1% of
subjects developed fluid retention that resolved after the TZD was discontinued. The research, which
appeared in the April 16, 2003, issue of the Journal of the American College of Cardiology,
To reconcile the risks and benefits of TZDs in diabetic patients who either currently have CHF or
have significant CHF risk factors, the AHA and ADA released the current consensus statement based on
available evidence.
Study Highlights Weight gain is common with both rosiglitazone and pioglitazone and may be due to
both increased caloric retention as well as fluid retention. When combined with a sulfonylurea,
weight gain may vary between 1.8 to 2.9 kg. Weight gain is even more significant when TZDs are
combined with insulin (average gain, 2.3 - 5.4 kg). Edema is also frequently found in patients
taking TZDs, occurring in 3% to 5% of patients using TZDs as monotherapy. Rates of edema are higher
if TZDs are used in combination with other hypoglycemic agents. 13.1% to 16.2% of patients taking
TZDs with insulin may experience edema. CHF is not frequently encountered with TZD use.
Rosiglitazone, either alone or in combination with other oral hypoglycemic agents, is associated
with an incidence of CHF of less than 1%. However, CHF incidence rises to 2% to 3% if rosiglitazone
is combined with insulin. Pioglitazone has been associated with an incidence of CHF of 1.1%. In
reviewing case reports of CHF associated with the use of TZDs, the authors of the consensus
statement caution that TZDs may unmask previously asymptomatic cardiac insufficiency by increasing
plasma volume. The recommendations of the consensus panel are as follows: Before prescribing a TZD,
the physician should perform a thorough history and physical for risk factors, such as previous
myocardial infarction or significant valvular disease, that could predispose a patient to CHF.
Baseline dyspnea and edema should be recorded. Physicians should also pay attention to other
medications, such as vasodilators, which may also contribute to fluid retention. Peripheral edema
is not a contraindication for TZD use, but it should be monitored during TZD therapy. Patients
should be instructed to report any weight gain more than 3 kg, new pedal edema, dyspnea, or fatigue
after starting a TZD. In patients without known heart disease but with 1 or more cardiac risk
factors, TZDs should be started at the lowest possible dose and advanced cautiously with special
attention to possible fluid overload. TZDs should be avoided if possible when the patient has a
known reduced ejection fraction (<40%) but is asymptomatic. Again, if TZDs must be used, the
patient should be started on the lowest possible dose and advanced cautiously. TZDs also may be
used with close patient supervision if the patient has known class I or II New York Heart Heart
Association (NYHA) CHF. TZDs should be avoided in cases of class III or IV NYHA CHF. If evidence of
fluid overload manifests itself during TZD therapy, especially in the first few months of
treatment, the physician should mount a thorough investigation for CHF. This should include an
electrocardiogram, echocardiogram, and, possibly, serum evaluation for brain natriuretic peptide.
If CHF is not present in a patient receiving TZDs with evidence of fluid overload, other drugs that
may contribute to increased intravascular volume should be reconsidered. The TZD also may be
discontinued or modified to a lower dose. Angiotensin-converting enzyme inhibitors with or without
a thiazide diuretic may help to reduce edema. Any treatment-emergent CHF should prompt a
reconsideration of the use of a TZD. If the TZD is discontinued, symptoms of volume overload should
be expected to resolve fairly quickly, and diuretic therapy may be needed for only a short time.
Pearls for Practice TZDs offer diabetic patients benefits beyond lowering serum glucose. TZDs
frequently lead to fluid retention. All patients receiving TZDs should be monitored for symptoms
and signs of fluid retention. TZDs should be avoided in patients with moderate to severe CHF or
evidence of an ejection fraction less than 40%.