What are the recommendations for using pioglitazone (thiazolidinedione) in patients with type 2 diabetes (T2D) and a history of heart failure or at high risk for cardiovascular events according to the anticipated American Diabetes Association (ADA) 2026 guidelines?

Pioglitazone in Type 2 Diabetes with Heart Failure History or High Cardiovascular Risk

Pioglitazone is contraindicated in patients with established heart failure (NYHA Class III-IV) and should be avoided in patients at high risk for heart failure, including those with type 2 diabetes and a history of heart failure or multiple cardiovascular risk factors. 1, 2

Absolute Contraindications

• NYHA Class III and IV heart failure represents an absolute contraindication to pioglitazone, as these patients were excluded from pre-approval clinical trials 2
• The FDA drug label explicitly states pioglitazone is not recommended in patients with NYHA Class III and IV cardiac status 2

Strong Recommendations Against Use in High-Risk Patients

• The American Heart Association and Heart Failure Society of America explicitly recommend avoiding thiazolidinediones in patients at high risk for heart failure with diabetes, hypertension, hyperlipidemia, and coronary artery disease 1, 3
• Pioglitazone causes fluid retention through sodium retention at the distal nephron, leading to or exacerbating heart failure, with risk accentuated at higher doses and when combined with insulin 1, 4, 2
• In patients with established coronary artery disease but without known heart failure, pioglitazone must be used with extreme caution and vigilance for any signs of fluid overload 1

Evidence of Heart Failure Risk

• Pioglitazone increases heart failure hospitalization risk with a hazard ratio of 1.8 compared to sulfonylureas 4, 3
• In the PROactive trial, 5.7% of pioglitazone-treated patients experienced serious heart failure events versus 4.1% on placebo (p=0.007) 2, 5
• A post-marketing safety study in patients with NYHA Class II-III heart failure showed 9.9% hospitalization rate for heart failure with pioglitazone versus 4.7% with glyburide, with treatment differences observed from 6 weeks 2
• Edema occurs in 4.8% of patients on pioglitazone monotherapy versus 1.2% on placebo, increasing to 15.3% when combined with insulin versus 7.0% on insulin alone 3, 2
• Plasma volume expansion of approximately 1.8 mL/kg occurs with pioglitazone, resulting in hemoglobin decreases of 0.8-1.1 g/dL 3

Limited Exceptions: NYHA Class II with Strict Protocols

• If pioglitazone must be prescribed for patients with NYHA Class II systolic heart failure, initiate at the lowest approved dose (15 mg daily) 4, 2
• Dose escalation should occur gradually only after several months with careful monitoring for weight gain, edema, or signs of CHF exacerbation 4, 2
• Close observation for signs and symptoms of heart failure is required, particularly in the first 3 months of treatment 4
• Discontinuation or dose reduction must be considered if heart failure signs develop 2

Pre-Treatment Cardiac Assessment Requirements

Before prescribing pioglitazone to any patient, the following cardiac assessment is mandatory:

• History of heart failure (any NYHA class) 4
• Previous myocardial infarction 4
• Significant aortic or mitral valve disease 4
• Current medications causing fluid retention 4
• Baseline edema status 4
• Recent ECG results 4

Preferred Alternative Agents

• Metformin should be the initial therapy for patients with type 2 diabetes at high cardiovascular risk, as it is associated with weight neutrality and no fluid retention 1, 3
• SGLT-2 inhibitors may decrease risks of both cardiovascular events and heart failure and are ideal for this patient population, provided eGFR ≥30 mL/min/1.73m² 1, 3
• GLP-1 receptor agonists may decrease risk of cardiovascular events in patients at high cardiovascular risk 1

Additional Safety Concerns

• Pioglitazone increases fracture risk, particularly in women, with a hazard ratio of 2.13 for fractures versus sulfonylurea 4
• Weight gain ranging from 0.9-2.6 kg occurs with monotherapy doses of 15-45 mg daily 4
• Pioglitazone is generally not recommended in chronic kidney disease due to fluid retention potential 4
• Anemia risk is significantly increased with pioglitazone (MH-OR 2.56; 95% CI 1.55-4.21) 6

Clinical Decision Algorithm

For patients with established heart failure (any symptomatic class):

• Do not prescribe pioglitazone 1, 2
• Use metformin and/or SGLT-2 inhibitors as preferred agents 1, 3

For patients at high cardiovascular risk without heart failure:

• Avoid pioglitazone if multiple risk factors present (hypertension, hyperlipidemia, coronary artery disease) 1, 3
• Consider pioglitazone only if other agents are contraindicated or inadequate 6
• If prescribed, start at 15 mg daily with intensive monitoring 4, 2

For patients with prior stroke and insulin resistance (prediabetes, not established T2D):

• Pioglitazone may be considered for stroke prevention (24% relative risk reduction in IRIS trial), but only after excluding heart failure history and with careful cardiac assessment 4