Can I add pioglitazone to a diabetic patient on metformin and empagliflozin with poor glycemic control and no heart failure?

Pioglitazone Should Not Be Added to This Patient's Regimen Due to Risk of Heart Failure

Pioglitazone should not be added to this patient's regimen due to the significant risk of fluid retention and heart failure, even in patients without pre-existing heart failure. 1

Patient Risk Assessment

The patient is a 68-year-old diabetic woman with:

• Poor glycemic control (A1c 11%)
• Obesity (BMI 30)
• Currently on metformin 1g twice daily and empagliflozin 25mg
• No known heart failure

While the patient denies heart failure, this demographic profile places her at high risk for developing heart failure if pioglitazone is initiated.

Evidence Against Using Pioglitazone

Risk of Heart Failure

• Randomized controlled trials have consistently demonstrated that thiazolidinediones (TZDs) like pioglitazone are associated with increased rates of heart failure hospitalization, even in patients without baseline heart failure 1
• In the PROactive trial, pioglitazone was associated with an increased risk of heart failure events compared with placebo 1
• Both rosiglitazone and pioglitazone are associated with fluid retention and heart failure events 1

Specific Contraindications

• The FDA label for pioglitazone (ACTOS) includes a boxed warning regarding the risk of congestive heart failure 2
• In clinical trials, 15.3% of patients on combination therapy with insulin developed edema compared to 7.0% on insulin alone 2
• Even as monotherapy, edema was reported in 4.8% of patients treated with pioglitazone versus 1.2% with placebo 2

Better Alternative Options

For this patient with poor glycemic control (A1c 11%) who is already on metformin and empagliflozin, better alternatives include:

1. GLP-1 receptor agonist:

   • Recommended by guidelines for patients with diabetes at high risk for cardiovascular disease 1
   • May decrease risk of cardiovascular events 1
   • Does not cause fluid retention or increase heart failure risk

2. DPP-4 inhibitor:

   • Could be considered if GLP-1 RA is not appropriate
   • Note that some (but not all) DPP-4 inhibitors may increase risk of heart failure hospitalization 1

3. Insulin therapy:

   • If other options fail to achieve glycemic control
   • Should be used with caution and close monitoring due to risk of hypoglycemia and weight gain 1

Clinical Decision Algorithm

1. First choice: Add a GLP-1 receptor agonist with proven cardiovascular benefit

   • Examples: liraglutide, semaglutide, dulaglutide 1
   • Benefits: weight loss, reduced cardiovascular risk, potent A1c lowering

2. Second choice: Consider a DPP-4 inhibitor (preferably sitagliptin)

   • Less potent than GLP-1 RAs but weight neutral
   • Sitagliptin has shown no increased heart failure signal 1

3. Third choice: Insulin therapy if unable to achieve adequate glycemic control with other options

   • Start with basal insulin
   • Monitor closely for hypoglycemia and weight gain

Important Caveats

• The American Heart Association and American Diabetes Association explicitly warn against using TZDs in patients at risk for heart failure 1
• The patient's age (68) and BMI (30) increase her risk for developing heart failure with pioglitazone
• Even though she has no known heart failure, the risk of developing it with pioglitazone is substantial
• The patient's very poor glycemic control (A1c 11%) requires effective intervention, but safer alternatives exist

In conclusion, adding pioglitazone to this patient's regimen poses an unnecessary risk of developing heart failure. A GLP-1 receptor agonist would be a more appropriate addition to improve glycemic control while potentially providing cardiovascular benefits.