How do DPP-4 (Dipeptidyl Peptidase-4) inhibitors cause nasopharyngitis?

DPP-4 Inhibitors and Nasopharyngitis: Mechanism of Action

DPP-4 inhibitors increase the risk of nasopharyngitis through their immunomodulatory effects, particularly by altering immune responses in the upper respiratory tract. This side effect is well-documented in clinical trials and post-marketing surveillance.

Immunological Mechanism

DPP-4 (dipeptidyl peptidase-4) is not only involved in glucose regulation but also plays important roles in immune function. Here's how DPP-4 inhibitors may cause nasopharyngitis:

1. Altered Immune Function:

   • DPP-4 (also known as CD26) is expressed on various immune cells and has important immunoregulatory functions 1
   • Inhibition of DPP-4 may disrupt normal immune responses in the upper respiratory tract

2. Mast Cell Involvement:

   • DPP-4 inhibitors can affect mast cell activation and degranulation 2
   • While sitagliptin has been shown to reduce mast cell activation in allergic rhinitis models, the alteration of normal mast cell function may contribute to increased susceptibility to infections

3. Increased Susceptibility to Infections:

   • A disproportionality analysis using the WHO adverse drug reaction database found that DPP-4 inhibitors were associated with significantly higher reporting of infections compared to other antidiabetic drugs 1
   • The reporting odds ratio for upper respiratory tract infections was particularly high at 12.3 (95% CI 8.6-17.5) 1

Clinical Evidence

Nasopharyngitis is consistently reported as one of the most common adverse effects of DPP-4 inhibitors:

• Multiple clinical trials and meta-analyses have identified nasopharyngitis as one of the most frequently reported adverse events with DPP-4 inhibitors 3
• A systematic review of DPP-4 inhibitors found that rates of nasopharyngitis were higher with DPP-4 inhibitors compared to placebo 3
• This side effect has been observed across different DPP-4 inhibitors, including sitagliptin, saxagliptin, linagliptin, and others 4

Risk Assessment and Management

When considering DPP-4 inhibitors for diabetes management:

• Risk Awareness: Nasopharyngitis, while common, is generally mild and self-limiting
• Patient Selection: Consider alternative agents in patients with recurrent upper respiratory infections
• Monitoring: Be vigilant for symptoms of upper respiratory infections in patients taking DPP-4 inhibitors
• Benefit-Risk Assessment: The European Society of Cardiology notes that some DPP-4 inhibitors (sitagliptin and linagliptin) have a neutral effect on heart failure hospitalization and may be considered for diabetes treatment in patients with heart failure 5

Clinical Considerations

When prescribing DPP-4 inhibitors:

• Inform patients about the increased risk of nasopharyngitis as a potential side effect
• Consider that saxagliptin specifically carries a warning regarding increased risk of heart failure hospitalization and is not recommended for patients at risk of heart failure 5
• Be aware that other common adverse effects include headache, gastrointestinal symptoms, and musculoskeletal pain 3

Conclusion

The mechanism by which DPP-4 inhibitors cause nasopharyngitis likely involves their immunomodulatory effects, particularly on immune cells in the upper respiratory tract. While this side effect is common, it is generally not severe enough to warrant discontinuation of therapy in most patients, but should be considered in the overall benefit-risk assessment when selecting antidiabetic therapy.