Is it reasonable to start pioglitazone (thiazolidinedione) 7.5 mg once daily in a patient with diabetes, hemoglobin A1c (HbA1c) of 7.8%, on Tresiba (insulin degludec) 20 units once daily, metformin 2.5 grams daily, empagliflozin (SGLT2 inhibitor) 25 mg once daily, and valsartan (angiotensin II receptor antagonist) 80 mg twice daily, with no signs or symptoms of heart failure (HF) and no established atherosclerotic cardiovascular disease (ASCVD)?

Pioglitazone Should Not Be Started in This Patient

Given this patient's current regimen already includes empagliflozin (an SGLT2 inhibitor with proven cardiovascular and renal benefits), adding pioglitazone is not reasonable and carries unnecessary risk of heart failure without providing superior glycemic benefit. 1

Why Pioglitazone Is Not the Right Choice

Heart Failure Risk Without Established Benefit

• Pioglitazone causes fluid retention and can precipitate or worsen heart failure, even in patients without prior HF symptoms. 2
• The FDA label explicitly warns that thiazolidinediones like pioglitazone cause fluid retention when used alone or with other antidiabetic agents, and this may lead to or exacerbate heart failure. 2
• In a controlled study of patients with type 2 diabetes and systolic dysfunction (NYHA Class II/III), pioglitazone was associated with a 13% incidence of heart failure events versus 8% with glyburide (p=0.024), with higher rates of hospitalization or emergency room visits for HF. 3
• The PROactive trial showed 5.7% of pioglitazone-treated patients experienced serious heart failure versus 4.1% on placebo. 2

Superior Alternatives Already Available

• The patient is already on empagliflozin 25 mg, which provides superior cardiovascular and renal protection compared to pioglitazone. 1
• The 2024 DCRM guidelines position GLP-1 receptor agonists and SGLT2 inhibitors above pioglitazone in treatment hierarchies for patients with or at risk for cardiovascular disease. 1
• For this patient with HbA1c 7.8% (above the 7% target), adding a GLP-1 receptor agonist would provide 0.6-0.8% additional HbA1c reduction with cardiovascular benefits and weight loss, rather than the fluid retention and HF risk of pioglitazone. 1, 4

The Correct Treatment Intensification Strategy

First-Line Intensification: Add GLP-1 Receptor Agonist

• For patients on metformin, SGLT2 inhibitor, and basal insulin with HbA1c still above target, a GLP-1 receptor agonist is the preferred next agent. 1
• GLP-1 receptor agonists provide HbA1c reduction of 0.6-0.8% when added to existing therapy, with proven cardiovascular benefits in patients at high CV risk. 4, 5
• Unlike pioglitazone, GLP-1 receptor agonists cause weight loss rather than weight gain and have minimal hypoglycemia risk. 4
• The 2024 ADA guidelines recommend introducing GLP-1 receptor agonists in people with CVD risk factors independent of baseline A1C for cardiovascular benefit. 1

Second-Line Option: Optimize Basal Insulin

• The current Tresiba dose of 20 units may be suboptimal for this patient's glycemic control. 4
• Titrate basal insulin by 2-4 units every 3-7 days until fasting glucose reaches target, with careful monitoring to avoid hypoglycemia. 4
• The maximum basal insulin dose should not exceed approximately 0.5 units/kg/day to avoid overbasalization. 4

Why Not Pioglitazone Even at Low Dose

• While the proposed 7.5 mg dose is lower than typical starting doses, the FDA label makes no distinction for "low-dose" safety regarding heart failure risk—fluid retention occurs at all doses. 2
• A 2023 study comparing empagliflozin and pioglitazone in patients with type 2 diabetes and NAFLD (without established ASCVD) showed both improved left ventricular function, but empagliflozin was more effective at reducing liver steatosis. 6 However, this does not justify adding pioglitazone when empagliflozin is already on board.
• The patient already has the metabolic benefits of an insulin sensitizer through metformin, making pioglitazone's mechanism redundant. 1

Critical Monitoring If Pioglitazone Were Considered (Which It Should Not Be)

If a clinician were to proceed against this recommendation:

• Monitor closely for signs and symptoms of heart failure: dyspnea, orthopnea, edema, rapid weight gain (>2-3 kg in one week). 2
• Discontinue pioglitazone immediately if any signs of heart failure develop. 2
• Pioglitazone is contraindicated in patients with NYHA Class III or IV heart failure. 2, 7
• The risk of heart failure hospitalization increases when pioglitazone is combined with insulin, as this patient would be receiving. 2

Bottom Line Algorithm

For this patient with HbA1c 7.8% on metformin, empagliflozin, and basal insulin:

1. Add a GLP-1 receptor agonist (liraglutide 1.8 mg daily or semaglutide 1 mg weekly preferred based on cardiovascular outcome data) 1, 4
2. Optimize basal insulin dose by titrating upward if fasting glucose remains elevated 4
3. Reassess HbA1c in 3 months to determine if further intensification is needed 4
4. Do not add pioglitazone due to heart failure risk without incremental benefit over the current evidence-based regimen 2, 3, 7