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Do DPP-4 Inhibitors Increase Risk of Pneumonia in Patients with T2D?

Oct 17, 2020
 
Editor: Steve Freed, R.PH., CDE

Author: Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences

Since DPP-4 plays a role in infection for some coronaviruses, there is increased interest in whether patients using DPP-4 inhibitors are at greater pneumonia risk. 

DPP-4 inhibitors are a class of commonly used antihyperglycemic agents. DPP-4 cleaves incretin hormones, and other substrates including cytokines and chemokines, that regulate innate immunity and inflammation. Patients with diabetes have an increased risk of developing pneumonia, including viral pneumonia. There is an interest in the potential of increased pneumonia risk in patients using DPP-4 inhibitors, since DPP-4 plays a role in infection for some coronaviruses. A new observational study aimed to determine if DPP-4 inhibitors increase the risk of pneumonia in diabetes patients. Meta-analyses were also performed to provide further evidence for their research. 

For the observational studies, administrative data was pulled from the Italian Veneto regional Health Information Exchange system. The second cohort’s clinical data were drawn from the University Hospital of Padova outpatient diabetes clinic in northern Italy. Propensity score-matched analysis was performed to analyze patients’ hospitalization rates taking second-line hyperglycemic medication versus new users of DPP-4 inhibitors not currently taking any of the other therapies being studied, matching patients 1:1. The studies included patients with T2D diagnosis and taking antihyperglycemic medication before the start of the analysis. The outcome for the observed data was hospitalization for pneumonia indicated by ICD codes. 

For the observational data, Cox proportional HRs with 95% CI were used to compare the outcome of pneumonia incidence between new users of DPP-4 inhibitors and patients taking second-line therapy (sulfonylureas, pioglitazone, or SGLT-2 inhibitors). An intention-to-treat (ITT) analysis censored at the time of outcome or death and an as-treated analysis also edited to include last observation, treatment withdrawal, or the initiation of another antihyperglycemic drug being observed in the study were conducted for both databases. 

For the meta-analyses, searches for both the observational and RCT studies were conducted for English language literature that looked at the association of pneumonia incidence and DPP-4 inhibitors. RCTs were included in the analysis if the duration was ≥ one year, if ≥ 100 patients were enrolled and if they reported the incidence of pneumonia. For both meta-analyses, risk of bias was assessed using the Cochrane tool, and pooled risk ratios were obtained using the random effect model.  

From the administrative database, 6495 new DPP-4 inhibitors users were matched with patients starting second-line antihyperglycemic agents. The match included 4802 sulfonylurea, 657 pioglitazone, and 1036 SGLT-2 inhibitors patients. In the ITT analysis, patients taking DPP-4 inhibitors were at a 24% lower risk of being hospitalized for pneumonia (HR 0.76, 95% CI 0.61-0.95; p=0.015). In the as-treated population, the risk reduction was even lower at 31% (HR 0.69, 95% 0.54-0.88; p=0.003). 

The same risk reduction was not confirmed in the clinical database. In this database, 2535 new users of DPP-4 inhibitors were matched 1:1 with 1237 sulfonylurea, 144 pioglitazone, and 115 SGLT-2 inhibitor patients. Though the crude unadjusted HR was significant for a reduced risk of pneumonia hospitalization in the DPP-4 inhibitor group (0.62, 95% CI, 0.43-0.91), the number of patients in the study at that time had dropped significantly, prompting the addition of 867 more patients in each group who were matched. The overall risk reduction in the DPP-4 inhibitor group was not statistically significant in either the ITT (HR 0.65, 95% CI 0.41-1.04) or the as-treated analyses (HR 0.58, 95& CI 0.28-1.18) vs. comparators. 

The observational meta-analysis was comprised of 2 observational studies retrieved from literature and the results from the administrative data found in this study, for a total of 193,545 patients observed. Two studies showed significantly lower pneumonia rates in patients taking DPP-4 inhibitors, while one study did not. When all three observational studies were meta-analyzed, the risk of pneumonia was lower in the DPP-4 inhibitor groups than comparators, though not significantly (RR 0.81; 95% CI 0.65-1.01). 

The meta-analysis of RCTs contained 41 studies, for a total of 78,478 patients included in the analysis. The RCTs’ quality was high, with a low risk of bias in most studies. Compared to placebo or active comparators, patients taking DPP-4 inhibitors were found to have an increased risk of pneumonia, though this risk was not found to be significant (RR 1.06; 95% CI 0.93-1.20). 

Though the administrative observational study did show a 24% reduction in risk of pneumonia in patients taking DPP-4 inhibitors, the overall data concluded that DPP-4 inhibitors do not reduce or increase the risk of pneumonia in patients with diabetes. The data suggest that these drugs should not cause concern for increased pneumonia risk. 

Practice Pearls: 

  • An administrative observational study found that DPP-4 inhibitors reduced the risk of pneumonia by 24% though meta-analyses results differ. 
  • Overall data concluded that DPP-4 inhibitors do not reduce or increase the risk of pneumonia in diabetes patients. 
  • There is no concern for increased pneumonia risk in patients taking DPP-4 inhibitors. 

 

Fadini, Gian Paolo, et al. “Exposure To DipeptidylPeptidase 4 Inhibitors And The Risk Of Pneumonia Among People With Type 2 Diabetes: Retrospective Cohort Study And MetaAnalysis”. Diabetes, Obesity, And Metabolism, vol 22, no. 10, 2020, pp. 1925-1934. Wiley, https://doi.org/10.1111/dom.14142. Accessed 22 Sept 2020. 

Wvan der ZandenRogier et al. “Use Of Dipeptidyl-Peptidase-4 Inhibitors And The Risk Of Pneumonia: A Population-Based Cohort Study”. PLOS ONE, vol 10, no. 10, 2015, p. e0139367. Public Library Of Science (Plos), https://doi.org/10.1371/journal.pone.0139367. Accessed 24 Sept 2020. 

 

Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences