In a 67-year-old patient with uncontrolled type 2 diabetes, hypertension, dyslipidemia, NYHA Class III heart failure, atherosclerotic cardiovascular disease, chronic kidney disease, and COPD who is on metformin and basal insulin, which medication should be avoided: pioglitazone, liraglutide, empagliflozin, or sitagliptin?

Avoid Pioglitazone in This Patient

Pioglitazone must be avoided in this patient due to their NYHA Class III heart failure, as thiazolidinediones are contraindicated in all patients with established symptomatic heart failure. 1, 2

Why Pioglitazone is Contraindicated

Heart Failure Concerns

• The American Heart Association explicitly states that thiazolidinediones (including pioglitazone) are contraindicated in any patient with symptomatic heart failure, regardless of functional class. 1, 2
• Pioglitazone causes fluid retention through increased renal sodium reabsorption, leading to volume expansion and heart failure exacerbation. 2
• In patients with NYHA Class III heart failure, pioglitazone increases the risk of hospitalization for heart failure by 13% compared to 8% with alternative agents. 3
• The FDA Black Box Warning specifically states that thiazolidinediones may cause or exacerbate heart failure, and are not recommended for use in any patient with symptomatic heart failure. 1

Additional Risk Factors in This Patient

• The combination of pioglitazone with insulin (which this patient is taking) exacerbates fluid retention, with 5-15% of patients on combined therapy experiencing peripheral edema compared to only 2-5% on monotherapy. 4
• This patient's chronic kidney disease further increases the risk of fluid retention and volume overload when using thiazolidinediones. 1
• The presence of COPD creates additional concerns, as pulmonary edema has been reported with pioglitazone, especially in insulin-treated patients. 4

Why the Other Agents Are Acceptable

Empagliflozin (Preferred Option)

• SGLT-2 inhibitors like empagliflozin are actually recommended as first-line therapy in patients with heart failure and diabetes to reduce heart failure hospitalization risk. 2
• Empagliflozin provides cardiovascular benefit and is appropriate for this patient's ASCVD. 1

Liraglutide (Acceptable Option)

• GLP-1 receptor agonists like liraglutide show neutral effects on heart failure hospitalization in stable heart failure patients. 2
• Liraglutide has proven cardiovascular benefit and is recommended for patients with T2DM and ASCVD. 1
• While caution is advised in recent heart failure decompensation, it can be used in stable NYHA Class III patients. 2

Sitagliptin (Acceptable with Caution)

• DPP-4 inhibitors like sitagliptin can be used in CKD with dose adjustment. 1
• While saxagliptin increases heart failure hospitalization risk, sitagliptin has not shown the same signal and demonstrates overall neutral cardiovascular outcomes. 1, 5
• Sitagliptin requires dose reduction based on kidney function but remains a viable option. 1

Clinical Decision Algorithm

1. Immediately exclude pioglitazone due to NYHA Class III heart failure contraindication. 1, 2
2. Prioritize empagliflozin as the preferred add-on agent given its heart failure benefits and cardiovascular protection. 2
3. Consider liraglutide as second choice if SGLT-2 inhibitor is not tolerated or contraindicated. 1, 2
4. Reserve sitagliptin as third-line option if both empagliflozin and liraglutide cannot be used. 1