Why avoid Dipeptidyl Peptidase-4 (DPP4) inhibitors and Glucagon-like peptide-1 (GLP1) receptor agonists in certain patients with type 2 diabetes?

DPP-4 Inhibitors and GLP-1 Receptor Agonists: When to Avoid in Type 2 Diabetes

DPP-4 inhibitors should be avoided in patients with heart failure, while GLP-1 receptor agonists should be avoided in patients with recent heart failure decompensation. 1

DPP-4 Inhibitors: Reasons to Avoid

Heart Failure Concerns

• DPP-4 inhibitors, particularly saxagliptin, have been associated with increased risk of heart failure hospitalization 1
• The SAVOR TIMI-53 trial showed a 27% relative increase in heart failure hospitalization risk with saxagliptin 1
• According to the European Society of Cardiology (ESC) guidelines, saxagliptin is specifically not recommended for diabetes treatment in patients at risk of heart failure or with previous heart failure (Class III recommendation, Level B evidence) 1

Specific Patient Populations to Avoid DPP-4 Inhibitors:

• Patients with established heart failure (both HFrEF and HFpEF) 1
• Patients at high risk for heart failure 1
• Patients with previous heart failure hospitalization 1

Comparative Efficacy Concerns

• The American College of Physicians recommends against adding DPP-4 inhibitors to metformin due to high-certainty evidence showing they don't reduce morbidity and mortality 2
• DPP-4 inhibitors have higher risk of heart failure compared to GLP-1 receptor agonists (HR 1.22) and SGLT2 inhibitors (HR 1.81) 1
• Network meta-analysis shows SGLT2 inhibitors probably reduce progression to CKD compared to DPP-4 inhibitors (RR 0.62) 1

GLP-1 Receptor Agonists: Reasons to Avoid

Heart Failure Concerns

• GLP-1 receptor agonists should be avoided in patients with recent heart failure decompensation 1
• Small randomized controlled trials showed a trend toward worse outcomes with liraglutide in patients with established HFrEF 1

Specific Patient Populations to Avoid GLP-1 Receptor Agonists:

• Patients with history of pancreatitis 1
• Patients with history of gastroparesis 1
• Patients with history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2 (MEN2) 1, 3
• Patients with proliferative retinopathy (specifically for semaglutide) 1
• Patients with persistent nausea, even at low doses 1

Adverse Effects

• GI symptoms (nausea, vomiting, diarrhea) are common and may lead to hemodynamic derangement 4
• Injection site reactions, headache, and nasopharyngitis are common 4
• May increase heart rate by 3-10 beats/minute 1

Clinical Decision Algorithm

1. For patients with established heart failure or at high risk:

   • Avoid DPP-4 inhibitors, especially saxagliptin 1
   • Avoid GLP-1 receptor agonists if recent heart failure decompensation 1
   • Consider SGLT2 inhibitors as preferred option (Class I recommendation) 1

2. For patients with renal impairment:

   • DPP-4 inhibitors may be considered with appropriate dose adjustments (except linagliptin which doesn't require adjustment) 2
   • GLP-1 receptor agonists can be used when eGFR is consistently <45 ml/min/1.73m² 1

3. For patients with specific comorbidities:

   • Avoid GLP-1 receptor agonists in patients with history of pancreatitis, gastroparesis, MEN2, or medullary thyroid cancer 1, 3
   • Consider DPP-4 inhibitors in patients who cannot tolerate GI side effects of GLP-1 receptor agonists 4

Important Caveats and Considerations

• Not all DPP-4 inhibitors carry the same heart failure risk - sitagliptin and linagliptin have shown a neutral effect on heart failure hospitalization 1
• When initiating either class of medication in patients on insulin or sulfonylureas, consider reducing doses of these agents by 20-50% to prevent hypoglycemia 1
• The risk of intestinal obstruction with both DPP-4 inhibitors and GLP-1 receptor agonists appears to be minimal based on recent Scandinavian cohort data 5
• Despite concerns about pancreatic cancer risk with incretin-based therapies, meta-analyses have not confirmed a causal relationship 4

By carefully considering these contraindications and precautions, clinicians can optimize diabetes therapy while minimizing cardiovascular and other risks in patients with type 2 diabetes.