The Roles of Dipeptidyl Peptidase 4 (DPP4) and DPP4 Inhibitors in Different Lung Diseases: New Evidence

CD26/Dipeptidyl peptidase 4 (DPP4) is a type II transmembrane glycoprotein that is widely expressed in various organs and cells. It can also exist in body fluids in a soluble form. DPP4 participates in various physiological and pathological processes by regulating energy metabolism, inflammation, and immune function. DPP4 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. More evidence has shown the role of DPP4 in the pathogenesis of lung diseases, since it is highly expressed in the lung parenchyma and the surface of the epithelium, vascular endothelium, and fibroblasts of human bronchi. It is a potential biomarker and therapeutic target for various lung diseases. During the coronavirus disease-19 (COVID-19) global pandemic, DPP4 was found to be an important marker that may play a significant role in disease progression. Some clinical trials on DPP4 inhibitors in COVID-19 are ongoing. DPP4 also affects other infectious respiratory diseases such as Middle East respiratory syndrome and non-infectious lung diseases such as pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and asthma. This review aims to summarize the roles of DPP4 and its inhibitors in infectious lung diseases and non-infectious diseases to provide new insights for clinical physicians.

Unmasking Fracture Risk in Type 2 Diabetes: The Association of Longitudinal Glycemic Hemoglobin Level and Medications

Context Fracture risk is underestimated in people with type 2 diabetes (T2D). Objective To investigate the longitudinal relationship of glycated hemoglobin (HbA1c) and common medications on fracture risk in people with T2D. Design Retrospective cohort study was conducted using de-identified claims and EHR data obtained from the OptumLabs ® Data Warehouse during 01/01/2007 to 09/30/2015. For each individual, the study was conducted within a two-year HbA1c observation period and a two-year fracture follow-up period. Setting Population-based study. Participants 157,439 individuals with T2D [age ≥ 55 years with mean HbA1c value ≥ 6%] were selected from 4,018,250 US Medicare Advantage/Commercial enrollee with T2D diagnosis. Main Outcome Measures. All fractures and fragility fractures were measured. Results With covariates adjusted, poor glycemic control in T2D individuals was associated with an 29% increase of all fracture risk, compared to T2D individuals with adequate glycemic control (HR: 1.29, 95% CI 1.22-1.36). Treatment with metformin (HR: 0.88, 95% CI 0.85-0.92) and DPP4 inhibitors (HR: 0.93, 95% CI 0.88-0.98) were associated with a reduced all fracture risk, while insulin (HR: 1.26, 95% CI 1.21-1.32), thiazolidinediones (HR: 1.23, 95% CI 1.18-1.29), meglitinides (HR: 1.12, 95% CI 1.00-1.26) were associated with an increased all fracture risk (All p-value < 0.05). Bisphosphonates were associated similarly with increased fracture risk in T2D group and in non-diabetic group. Conclusions Longitudinal two-year HbA1c is independently associated with an elevated all fracture risk in T2D individuals during a two-year follow-up period. Metformin and DPP4 inhibitors can be used for management of T2D fracture risk.

Genetic Insights into the Middle East Respiratory Syndrome Coronavirus Infection among Saudi People

Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) was isolated for the first time in Saudi Arabia from a patient suffering from atypical pneumonia. The Saudi Genome database was built by King Abdulaziz Medical City via the next-generation sequencing of 7000 candidates. Method: A large list of point mutations were reported in the region of the dipeptidyl peptidase 4 (DPP4) gene. The DPP4 amino acid residues correlated to MERS-CoV entry and the site of activity of DPP4 inhibitors was investigated. We retrieved the SNPs (Single-Nucleotide Polymorphism) with a variation frequency of >0.05. Results: SNP 2:162,890,175 and SNP 2:162,891,848 in the intronic region were located within 50 bp of amino acid residues responsible for MERS-CoV entry, amino acids 259–296 and 205–258, respectively. The variation frequency of SNP 2:162,890,175 was 2321 out of 2379 screened individuals. Moreover, mutation of SNP 2:162,891,848, which is located near amino acid residues E205 and E206 (crucial for the activity of DPP4 inhibitors), occurred in 76 out of 2379 screened individuals. Conclusions: Our study shows high variation frequency in the DPP4 region reported in the Saudi Genome database. The identified SNPs are of high significance for MERS-CoV infection in better understanding disease pathogenesis.

Antidiabetic drugs use and new-onset atrial fibrillation in patients with diabetes mellitus

Background Diabetes is one of the most common chronic disorders worldwide and is an important cause of cardiovascular disease. Large studies investigating the risk of atrial fibrillation (AF) in diabetic patients taking different diabetes medications are still missing. Methods The analysis was based on the EGB (“Echantillon Généraliste des Bénéficiaires”) database, a 1/97 representative sample of the French nationwide claims and hospitalisation database. A cohort comprising 25,117 adult patients with diabetes and no previous AF seen between 2010 and 2018 was created and followed until December 2018 for incidence of new-onset AF. Among these diabetic patients, 36.0% were treated with metformin, 32.0% were treated with Sulfonylureas, 7.0% were treated with DPP4-inhibitors, 1.6% were treated with GLP1- analogues and 19.6% were treated with insulin. A Cox proportional hazards model was used to determine factors and different oral diabetes medications independently associated with the risk of AF during follow-up. Results During a follow-up of 4.8±3.5 years, there were 3,300 patients with new onset AF (yearly rate 2.7%). In multivariable analysis, among baseline characteristics, we found that older age, male sex, hypertension, heart failure, aortic stenosis, chronic kidney disease, anemia and diuretic use were independently associated with a higher risk of new AF. Among diabetes medications included in the multivariable model, use of sulfonylureas was independently associated with a lower risk of AF (HR 0.86, 95% CI 0.80–0.92, p<0.0001 vs no use). By contrast, use of GLP1-analogues (HR 2.27, 95% CI 1.49–3.46, p=0.0001 vs no use), DPP4-inhibitors (HR 1.88, 95% CI 1.59–2.22, p<0.0001 vs no use), metformin (HR 1.09, 95% CI 1.01–1.18, p=0.03 vs no use) and of insulin (HR 1.15, 95% CI 1.05–1.26, p=0.004 vs no use) were independently associated with a higher risk of AF. Conclusions Patients with different diabetes medications have significantly different long-term risk of AF. Specifically, sulfonylureas use was associated with a lower risk of incident AF whilst other antidiabetic drugs were associated with a higher risk of AF during follow-up. FUNDunding Acknowledgement Type of funding sources: None.

DPP4 inhibitors as a risk factor for QTC interval prolongation among type 2 diabetic patients

Introduction Prolonged QT interval is associated with cardiac arrhythmias and sudden death. This study determined the prevalence of QT intervals corrected for heart rate (QTc) among adults admitted for executive check up in a tertiary hospital with Type 2 diabetes and its associations with metabolic control. Methods This cross-sectional study included 111 adult patients with Type 2 diabetes and 152 control patients admitted for executive check up in a tertiary hospital. A standard 12-lead electrocardiogram was recorded. Corrected QT interval (QTc) of >440 ms was considered abnormally prolonged and QTc >500 ms was considered a high-risk QTc. Demographic, clinical and laboratory data were collected. Independent risk factors for prolonged QTc were assessed using logistic regression analysis. Results QTc duration was statistically significant between subjects with Type 2 diabetes and control subjects (mean duration 434 vs 419 ms; P=0.003). Prevalence of prolonged QTc among type 2 diabetics is 41.4% and 28% in the control group. In the diabetic group 2.7% has a QTc of >500. Independent risk factors for prolonged QTc using univariate logistic regression analysis is presence of diabetes type 2 (OR = 2.00, p=0.008), HBA1c (OR = 1.23, p=0.050) and intake of DPP4 (OR=6.46, (p≤0.001). Independent risk factors for prolonged QTc using multivariate logistic regression analysis is intake of DPP4 inhibitors (OR=6.26, p=0.023). Conclusion There is no significant correlation between HBA1C and QTc interval. The prevalence of prolonged QTc is relatively high among diabetics but the prevalence of high risk QTc interval is relatively low. Intake of DPP4 inhibitors is an independent risk factor in QT prolongation. FUNDunding Acknowledgement Type of funding sources: None.

Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging

Vascular aging is characterized by alterations in the constitutive properties and biological functions of the blood vessel wall. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are indispensability elements in the inner layer and the medial layer of the blood vessel wall, respectively. Dipeptidyl peptidase-4 (DPP4) inhibitors, as a hypoglycemic agent, play a protective role in reversing vascular aging regardless of their effects in meliorating glycemic control in humans and animal models of type 2 diabetes mellitus (T2DM) through complex cellular mechanisms, including improving EC dysfunction, promoting EC proliferation and migration, alleviating EC senescence, obstructing EC apoptosis, suppressing the proliferation and migration of VSMCs, increasing circulating endothelial progenitor cell (EPC) levels, and preventing the infiltration of mononuclear macrophages. All of these showed that DPP4 inhibitors may exert a positive effect against vascular aging, thereby preventing vascular aging-related diseases. In the current review, we will summarize the cellular mechanism of DPP4 inhibitors regulating vascular aging; moreover, we also intend to compile the roles and the promising therapeutic application of DPP4 inhibitors in vascular aging-related diseases.