Which oral antihyperglycemic agents should be avoided in patients with heart failure?

Oral Antihyperglycemic Agents to Avoid in Heart Failure

Thiazolidinediones (glitazones) are absolutely contraindicated in all patients with heart failure and should never be prescribed, as they increase the risk of heart failure worsening and hospitalization. 1

Primary Agents to Avoid

Thiazolidinediones (TZDs) - Class III Contraindication

Both pioglitazone and rosiglitazone are not recommended in patients with heart failure due to increased risk of fluid retention, heart failure hospitalization, and potentially death. 1

• TZDs cause fluid retention through increased renal sodium and water reabsorption, leading to volume expansion and heart failure decompensation 1, 2
• The contraindication applies to all patients with symptomatic heart failure regardless of NYHA functional class 1, 2
• TZDs should also be avoided in patients at high risk of developing heart failure, even without established disease 1, 2
• Rosiglitazone doubles the risk of heart failure hospitalization (HR 2.10,95% CI 1.35-3.27) with an excess of 2.6 heart failure events per 1000 person-years 3
• Pioglitazone increases heart failure hospitalization rates (13% vs 8% with glyburide, p=0.024) without improving cardiac function 4

Saxagliptin (DPP-4 Inhibitor) - Not Recommended

Saxagliptin significantly increases heart failure hospitalization risk and is not recommended in patients with heart failure or at high risk for heart failure. 1, 2

• This is the only DPP-4 inhibitor with demonstrated harm in heart failure 1
• Other DPP-4 inhibitors (sitagliptin, linagliptin) show neutral effects and may be considered if needed 1
• Alogliptin showed a non-significant trend toward increased heart failure hospitalization and should be used cautiously 1, 5

Agents to Use with Extreme Caution

NSAIDs and COX-2 Inhibitors

NSAIDs and COX-2 inhibitors are not recommended in heart failure patients as they increase risk of heart failure worsening and hospitalization. 1

Insulin

Insulin may be considered in advanced systolic heart failure but requires caution due to associations with weight gain, hypoglycemia, and potential increased mortality in observational studies. 1, 2

Preferred Alternatives in Heart Failure

First-Line: SGLT-2 Inhibitors (Class I Recommendation)

SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) are recommended as first-line therapy to reduce heart failure hospitalization risk by 32-35%. 1, 2

• These agents reduce heart failure hospitalization in patients with and without established heart failure 1
• Benefits extend across the entire ejection fraction spectrum 6

Second-Line: Metformin

Metformin should be considered if eGFR is stable and >30 mL/min/1.73 m². 1, 2

Neutral Options: GLP-1 Receptor Agonists

GLP-1 receptor agonists (lixisenatide, liraglutide, semaglutide, exenatide, dulaglutide) show neutral effects on heart failure hospitalization and may be considered. 1, 2

Clinical Decision Algorithm

For patients with established heart failure:

1. Immediately discontinue TZDs if currently prescribed 2
2. Avoid saxagliptin 1, 2
3. Initiate SGLT-2 inhibitor as first-line diabetes therapy 1, 2
4. Add metformin if eGFR >30 mL/min/1.73 m² 1, 2
5. Consider GLP-1 agonists or neutral DPP-4 inhibitors (sitagliptin, linagliptin) if additional therapy needed 1

For patients at high risk of heart failure (elderly, obese, hypertensive, microalbuminuria):

1. Never initiate TZDs 1, 2, 3
2. Avoid saxagliptin 1, 2
3. Prefer SGLT-2 inhibitors and metformin 1, 2
4. Monitor closely for signs of fluid retention: weight gain >2 kg in 1 week, peripheral edema, dyspnea 2, 7

Critical Pitfalls to Avoid

• Do not assume mild edema is acceptable with TZDs - even mild fluid retention can progress to overt heart failure 7, 8
• Do not continue TZDs in patients who develop any signs of heart failure - discontinuation is mandatory 1, 2, 3
• Do not overlook that 40% of patients currently on TZDs have contraindications including diagnosed heart failure, reduced ejection fraction, or loop diuretic use 8
• Age, obesity (BMI), microalbuminuria, and elevated systolic blood pressure are independent predictors of heart failure with TZDs - these patients require extra vigilance 3