What is the association between Pioglitazone (Thiazolidinedione) and cardiac risk?

From the Guidelines

Pioglitazone should be used with caution in patients with cardiovascular disease, as it carries a moderate cardiac risk profile, and its use is contraindicated in patients with established heart failure (NYHA Class III or IV) due to the risk of fluid retention and worsening heart failure symptoms. According to the most recent guidelines, patients with cardiovascular disease but without heart failure can be prescribed pioglitazone with regular monitoring 1. The typical dosage is 15-30 mg once daily, with a maximum of 45 mg daily. Before starting treatment, it is essential to assess baseline cardiac function and monitor for signs of fluid retention, weight gain, and edema during therapy 1. Patients should be instructed to report any new or worsening shortness of breath, rapid weight gain, or edema.

Some key points to consider when prescribing pioglitazone include:

• Regular cardiac monitoring every 3-6 months is recommended for patients on long-term therapy, especially those with additional cardiovascular risk factors 1.
• Pioglitazone may have cardiovascular benefits in certain populations by improving lipid profiles and reducing inflammation, but this must be balanced against its fluid retention properties 1.
• The risk of heart failure is accentuated at higher doses and when the drug is used with insulin, and thus, it is crucial to be vigilant for any signs of fluid overload to reduce the risk of overt heart failure 1.
• In patients with stroke and insulin resistance, pioglitazone has been shown to produce a significant reduction in stroke or myocardial infarction, as demonstrated in the IRIS trial 1.

Overall, the decision to prescribe pioglitazone should be made on a case-by-case basis, taking into account the individual patient's cardiovascular risk profile and the potential benefits and risks of the medication 1.

From the FDA Drug Label

WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. In a 16-week, U. S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. In this study, two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1. 1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8. 8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4. 7% of patients on glyburide with a treatment difference observed from 6 weeks.

Cardiac Risk with Pioglitazone:

• Pioglitazone can cause fluid retention, which may lead to or exacerbate heart failure.
• The incidence of congestive heart failure was higher in patients treated with pioglitazone and insulin compared to insulin alone.
• Pioglitazone is not recommended in patients with NYHA Class III and IV cardiac status.
• Patients with a history of cardiovascular conditions are at increased risk of developing congestive heart failure when treated with pioglitazone.
• Monitoring for signs and symptoms of heart failure is recommended when using pioglitazone, especially in patients with pre-existing cardiac conditions 2.

From the Research

Pioglitazone and Cardiac Risk

• The relationship between pioglitazone and cardiac risk is complex, with some studies suggesting a potential increased risk of heart failure, while others indicate improved cardiac outcomes 3, 4, 5, 6, 7.
• A study published in Circulation found that pioglitazone improved cardiac function and altered myocardial substrate metabolism in patients with well-controlled type 2 diabetes mellitus, without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism 3.
• The PROactive study found that pioglitazone was associated with an increased risk of serious heart failure events, but not with an increased risk of mortality due to heart failure 4.
• Another study published in Congestive Heart Failure found that pioglitazone did not significantly deteriorate cardiac function in patients with type 2 diabetes and mild cardiac disease, although it was associated with more heart failure, edema, and weight gain compared to glyburide 5.
• A review of the available evidence published in Cardiovascular Diabetology suggested that pioglitazone may have cardioprotective effects, including reduced risk of myocardial infarction and ischemic stroke, and improved cardiac remodeling and function 6.
• The safety profile of pioglitazone has been reviewed, with the main adverse effects reported being weight gain, pedal edema, bone loss, and precipitation of congestive heart failure in at-risk individuals, without any increase in cardiovascular or all-cause mortality 7.

Key Findings

• Pioglitazone may improve cardiac function and alter myocardial substrate metabolism in patients with type 2 diabetes mellitus 3.
• Pioglitazone is associated with an increased risk of serious heart failure events, but not with an increased risk of mortality due to heart failure 4.
• Pioglitazone may have cardioprotective effects, including reduced risk of myocardial infarction and ischemic stroke, and improved cardiac remodeling and function 6.
• The safety profile of pioglitazone is favorable, with the main adverse effects reported being weight gain, pedal edema, bone loss, and precipitation of congestive heart failure in at-risk individuals 7.