Why is Actos (Pioglitazone) not recommended in Heart Failure with Reduced Ejection Fraction (HFrEF)?

From the Guidelines

Actos (pioglitazone) is not recommended for patients with heart failure with reduced ejection fraction (HFrEF) due to its potential to worsen heart failure symptoms and increase fluid retention. This thiazolidinedione medication works by improving insulin sensitivity but has a significant side effect of causing sodium and water retention, which increases plasma volume. In patients with HFrEF who already have compromised cardiac function, this additional fluid burden can exacerbate heart failure, leading to increased edema, shortness of breath, and potentially hospitalization.

Key Points to Consider

• The European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure do not specifically mention Actos as a recommended treatment for HFrEF, instead focusing on other pharmacological treatments such as diuretics, sacubitril/valsartan, and ACE inhibitors 1.
• The guidelines do mention treatments that may cause harm in patients with symptomatic HFrEF, including certain calcium channel blockers and the addition of an ARB to an ACE-I and an MRA, but do not explicitly mention thiazolidinediones like Actos 1.
• Clinical studies have demonstrated that pioglitazone increases the risk of heart failure exacerbations and hospitalizations in vulnerable patients.
• For patients with diabetes and HFrEF, alternative glucose-lowering medications such as metformin, SGLT2 inhibitors (which actually benefit heart failure), or GLP-1 receptor agonists are generally preferred as they don't carry the same risks of fluid retention and heart failure worsening.

Recommendations for Practice

• Avoid using Actos in patients with established heart failure, particularly those with New York Heart Association (NYHA) Class III or IV heart failure.
• Consider alternative glucose-lowering medications for patients with diabetes and HFrEF.
• Monitor patients with HFrEF for signs of fluid retention and heart failure worsening when using any medication that may exacerbate these conditions.

From the FDA Drug Label

WARNING: CONGESTIVE HEART FAILURE Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated In a 24-week, dose-controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0. 9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108).

Actos is not good in HFref because it can cause or exacerbate congestive heart failure in some patients. The drug is not recommended in patients with symptomatic heart failure and is contraindicated in patients with established NYHA Class III or IV heart failure. Studies have shown that patients treated with Actos have a higher incidence of serious heart failure compared to those treated with placebo 22.

From the Research

Actos (Pioglitazone) in Heart Failure with Reduced Ejection Fraction (HFrEF)

• Actos, also known as pioglitazone, is a thiazolidinedione that has been associated with fluid retention, which can be problematic in patients with heart failure 3.
• A study published in the Journal of Cardiac Failure found that pioglitazone was associated with a higher incidence of hospitalization for heart failure compared to glyburide, although there was no increase in cardiovascular mortality or worsening cardiac function 3.
• The mechanism of action of thiazolidinediones, such as pioglitazone, is to increase insulin sensitivity, which can lead to fluid retention and potentially exacerbate heart failure symptoms 4.

Heart Failure with Reduced Ejection Fraction (HFrEF) Treatment

• HFrEF is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood, and is typically treated with a combination of medications, including beta blockers, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists 5, 6.
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors have also been shown to improve outcomes in patients with HFrEF, regardless of their diabetic status 5, 6.
• Pioglitazone is not typically recommended for patients with HFrEF due to its association with fluid retention and potential to exacerbate heart failure symptoms 3.

Alternative Treatment Options

• Other medications, such as SGLT2 inhibitors and vericiguat, have been shown to improve outcomes in patients with HFrEF and may be considered as alternative treatment options 5, 6.
• The choice of treatment for HFrEF should be individualized based on the patient's specific needs and medical history, and should be guided by current clinical guidelines and evidence-based practice 5, 6.