Salivary microbiota composition before and after use of proton pump inhibitors in patients with laryngopharyngeal reflux: a self-control study.

BACKGROUND: Issues associated with proton pump inhibitor (PPI) usage have been documented. PPIs affect the gastrointestinal microbiome, as well as the saliva microbiota of healthy individuals. However, the alterations in the saliva microbiota of laryngopharyngeal reflux (LPR) patients remain unclear. This study aims to examine the composition of saliva microbiota in LPR patients before and after PPI usage through a self-controlled study. METHODS: Thirty-two adult LPR patients participated in the study. Saliva samples were collected before and after an 8-week regimen of twice-daily administration of 20-mg esomeprazole. The impact of PPI administration on bacterial communities was assessed using 16 S rRNA gene sequencing. The functional and metabolic changes in saliva microbial communities after PPI usage were analyzed using PICRUSt2 based on our 16 S rRNA gene sequencing results. RESULTS: The alpha diversity within the salivary microbiota, as measured by the PD-whole-tree index, exhibited a significant difference between samples collected before and after PPI application (P = 0.038). Additionally, PCoA analysis of unweighted UniFrac distances (beta diversity) revealed distinct separation of saliva sample microbiota structures before and after PPI application in LPR patients, with statistical significance (Adonis test, R2 = 0.063, P< 0.010). Taxon-based analysis indicated that PPI administration increased the abundance of Epsilonproteobacteria, Campylobacterales, Campylobacteraceae, Campylobacter, and Campylobacter_gracilis, while reducing the abundance of Lactobacillaceae and Lactobacillus in salivary samples ( P< 0.050). Using LEfSe to compare bacterial abundances, Bacillaceae and Anoxybacillus were found to be enriched before PPI usage in LPR patients. Furthermore, the proportion of genes responsible for indole alkaloid biosynthesis in the salivary microbiota of LPR patients significantly increased after PPI therapy (P< 0.050). CONCLUSIONS: These findings indicate that PPIs induce alterations in the salivary microbiota of LPR patients. CHINESE CLINICAL TRIAL REGISTRY: No. ChiCTR2300067507. Registered on January 10,2023 retrospectively.

Quantitative Characterization of the Impact of Protein-Protein Interactions on Ligand-Protein Binding: A Multi-Chain Dynamics Perturbation Analysis Method.

Many protein-protein interactions (PPIs) affect the ways in which small molecules bind to their constituent proteins, which can impact drug efficacy and regulatory mechanisms. While recent advances have improved our ability to independently predict both PPIs and ligand-protein interactions (LPIs), a comprehensive understanding of how PPIs affect LPIs is still lacking. Here, we examined 63 pairs of ligand-protein complexes in a benchmark dataset for protein-protein docking studies and quantified six typical effects of PPIs on LPIs. A multi-chain dynamics perturbation analysis method, called mcDPA, was developed to model these effects and used to predict small-molecule binding regions in protein-protein complexes. Our results illustrated that the mcDPA can capture the impact of PPI on LPI to varying degrees, with six similar changes in its predicted ligand-binding region. The calculations showed that 52% of the examined complexes had prediction accuracy at or above 50%, and 55% of the predictions had a recall of not less than 50%. When applied to 33 FDA-approved protein-protein-complex-targeting drugs, these numbers improved to 60% and 57% for the same accuracy and recall rates, respectively. The method developed in this study may help to design drug-target interactions in complex environments, such as in the case of protein-protein interactions.

Homologous mapping yielded a comprehensive predicted protein-protein interaction network for peanut (Arachis hypogaea L.).

BACKGROUND: Protein-protein interactions are the primary means through which proteins carry out their functions. These interactions thus have crucial roles in life activities. The wide availability of fully sequenced animal and plant genomes has facilitated establishment of relatively complete global protein interaction networks for some model species. The genomes of cultivated and wild peanut (Arachis hypogaea L.) have also been sequenced, but the functions of most of the encoded proteins remain unclear. RESULTS: We here used homologous mapping of validated protein interaction data from model species to generate complete peanut protein interaction networks for A. hypogaea cv. 'Tifrunner' (282,619 pairs), A. hypogaea cv. 'Shitouqi' (256,441 pairs), A. monticola (440,470 pairs), A. duranensis (136,363 pairs), and A. ipaensis (172,813 pairs). A detailed analysis was conducted for a putative disease-resistance subnetwork in the Tifrunner network to identify candidate genes and validate functional interactions. The network suggested that DX2UEH and its interacting partners may participate in peanut resistance to bacterial wilt; this was preliminarily validated with overexpression experiments in peanut. CONCLUSION: Our results provide valuable new information for future analyses of gene and protein functions and regulatory networks in peanut.

NSAID-induced Gastric Ulcer Disease: A Deleterious Connection.

Gastric ulcers induced by non-steroidal anti-inflammatory drug (NSAID) usage have become a common public health problem, and several studies have established chronic NSAID usage to be one of the risk factors for the pathogenesis of peptic ulcers in patients. This review includes numerous articles that link NSAID usage with peptic mucosal erosion, especially among patients under anticoagulant therapy or with other risk factors. Risk factors for NSAID-induced peptic ulcers are reviewed, in addition to pathogenesis, clinical signs, symptoms, diagnosis, prevention, and treatments. We also emphasize effective methods for the prevention and management of peptic ulcers among NSAID users. Such methods include the use of selective Cyclo-oxygenase (COX-2) inhibitors as an alternative to aspirin or other Cyclo-oxygenase (COX-1) inhibitors, or using the lowest dosage possible in patients with other comorbidities. We have conducted a thorough review of the literature on diagnostic tests and alternative medication that can be used in the management of NSAID toxicity-induced ulcers.

Safety of potassium-competitive acid blockers in the treatment of gastroesophageal reflux disease.

INTRODUCTION: Proton pump inhibitors (PPIs) are the first-line treatment for gastroesophageal reflux disease (GERD). However, due to their intrinsic limitations, there are still unmet clinical needs that have fostered the development of potassium-competitive acid blockers (P-CABs). Currently, four different drugs (vonoprazan, tegoprazan, fexuprazan, and keverprazan) are marketed in some Asian countries, whereas only vonoprazan and tegoprazan are available in Western countries (USA and Brazil or Mexico, respectively). AREAS COVERED: This review summarizes the current knowledge on P-CABs acute and long-term safety in GERD treatment compared to that of PPIs. Full-text articles and abstracts were searched in PubMed. EXPERT OPINION: P-CABs proved to address some of the unmet clinical needs in GERD, with a favorable risk-benefit ratio compared to conventional PPIs. Preclinical and clinical findings have highlighted P-CAB safety to be superimposable, to that of PPIs, in short-term treatments, although further studies are warranted to monitor their effects in long-term therapy. From an epidemiological point of view, the paucity of rigorous data for many variables (e.g. age, ethnicity, drug interactions, comorbidities, genetic polymorphisms, interindividual susceptibility, and gut dysbiosis) deserves a worldwide framework of continuous pre/post-marketing pharmacovigilance programs to reduce potential confounding factors and accurately link acute and chronic P-CAB therapy to adverse outcomes.

Potassium-competitive Acid Blockers: Current Clinical Use and Future Developments.

PURPOSE OF THE REVIEW: Acid suppression with proton pump inhibitors (PPIs) represents the standard of care in the treatment of acid-related diseases. However, despite their effectiveness, PPIs display some intrinsic limitations, which underlie the unmet clinical needs that have been identified over the past decades. The aims of this review are to summarize the current status and future development of the new class of antisecretory drugs (potassium-competitive acid blockers, P-CABs) that have recently been introduced into medical practice. RECENT FINDINGS: Over the past decades, clinical needs unmet by the current acid suppressants have been recognized, especially in the management of patients with GERD, Helicobacter pylori infection and NSAID-related peptic ulcer. The failure to address these needs is mainly due to their inability to achieve a consistent acid suppression in all patients and, particularly, to control nighttime acidity. It was then realized that an extended duration of acid suppression would exert additional benefits. The available data with P-CABs show that they are able to address these unmet clinical needs. Four different P-CABs (vonoprazan, tegoprazan, fexuprazan and keverprazan) are currently available. However, only two of them are approved outside Asia. Vonoprazan is available in North, Central and South America while tegoprazan is marketed only in Latin American countries. Two other compounds (namely linazapran glurate and zestaprazan) are presently under clinical development. While clinical trials on GERD have been performed with all P-CABs, only vonoprazan and tegoprazan have been investigated as components of Helicobacter pylori eradication regimens. The available data show that-in the above two clinical indications-P-CABs provide similar or better efficacy in comparison with PPIs. Their safety in the short-term overlaps that of PPIs, but data from long-term treatment are needed.

A Comprehensive Review on the Efficacy and Safety of Vonoprazan in the Management of Gastric Acid-Related Diseases.

Gastric acid-related diseases, including gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and Helicobacter pylori (H. pylori) infection, present significant clinical challenges due to their prevalence and potential for severe complications. Effective management of these conditions is essential for symptom relief, mucosal healing, and prevention of complications. This review aims to evaluate the efficacy and safety of vonoprazan, a novel potassium-competitive acid blocker (P-CAB), in the treatment of gastric acid-related diseases and to compare it with traditional proton pump inhibitors (PPIs). A comprehensive analysis of clinical trials and studies was conducted to assess the effectiveness of vonoprazan in managing GERD, PUD, and H. pylori infection. The safety profile of vonoprazan was also reviewed, and comparisons were made to PPIs and other gastric acid suppressants. Vonoprazan demonstrates superior and more consistent acid suppression than PPIs, resulting in rapid and sustained symptom relief and mucosal healing. Clinical trials have shown its efficacy in treating GERD, PUD, and H. pylori infection, with higher eradication rates for H. pylori when used in combination therapies. The safety profile of vonoprazan is favorable, with fewer adverse effects and drug interactions compared to PPIs. Vonoprazan offers a promising alternative to traditional PPIs for the management of gastric acid-related diseases. Its unique mechanism of action and superior efficacy make it a valuable option for patients requiring effective and reliable acid suppression. Further research is warranted to explore its potential in broader clinical applications and to establish long-term safety data.

A network meta-analysis: evaluating the efficacy and safety of concurrent proton pump inhibitors and clopidogrel therapy in post-PCI patients.

Introduction: The objective of this research was to evaluate the risk of major adverse cardiovascular events (MACEs) associated with the use of various proton pump inhibitors (PPIs) in combination with clopidogrel in patients who underwent percutaneous coronary intervention (PCI). Methods: To accomplish this, we analyzed data from randomized controlled trials and retrospective cohort studies sourced from key electronic databases. These studies specifically examined the effects of different PPIs, such as lansoprazole, esomeprazole, omeprazole, rabeprazole, and pantoprazole, when used in conjunction with clopidogrel on MACEs. The primary focus was on the differential impact of these PPIs, while the secondary focus was on the comparison of gastrointestinal (GI) bleeding events in groups receiving different PPIs with clopidogrel vs. a placebo group. This study's protocol was officially registered with INPLASY (INPLASY2024-2-0009). Results: We conducted a network meta-analysis involving 16 studies with a total of 145,999 patients. Our findings indicated that rabeprazole when combined with clopidogrel, had the lowest increase in MACE risk (effect size, 1.05, 95% CI: 0.66-1.66), while lansoprazole was associated with the highest risk increase (effect size, 1.48, 95% CI: 1.22-1.80). Esomeprazole (effect size, 1.28, 95% CI: 1.09-1.51), omeprazole (effect size, 1.23, 95% CI: 1.07-1.43), and pantoprazole (effect size, 1.38, 95% CI: 1.18-1.60) also significantly increased MACE risk. For the secondary outcome, esomeprazole (effect size, 0.30, 95% CI: 0.09-0.94), omeprazole (effect size, 0.34, 95% CI: 0.14-0.81), and pantoprazole (effect size, 0.33, 95% CI: 0.13-0.84) demonstrated an increased potential for GI bleeding prevention. Conclusions: In conclusion, the combination of lansoprazole and clopidogrel was found to significantly elevate the risk of MACEs without offering GI protection in post-PCI patients. This study is the first network meta-analysis to identify the most effective regimen for the concurrent use of clopidogrel with individual PPIs. Systematic Review Registration: https://inplasy.com/inplasy-2024-2-0009/, identifier (INPLASY2024-2-0009).

Proton Pump Inhibitors Versus Histamine-2 Receptor Blockers for Stress Ulcer Prophylaxis on In-hospital Mortality Among Intensive Care Unit Patients Hospitalized for Major Adverse Cardiovascular and Cerebrovascular Events: Retrospective Cohort Study.

PURPOSE: Patients in the intensive care unit (ICU) commonly receive stress ulcer prophylaxis drugs, either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). The goal of this research was to evaluate the impact of these drugs on mortality among ICU patients hospitalized for major adverse cardiovascular and cerebrovascular events (MACCEs). METHODS: ICU patients hospitalized for MACCEs were sourced from the Medical Information Mart for Intensive Care-III database. We performed a propensity score matching analysis to match patients treated with PPIs to those treated with H2RBs for stress ulcer prophylaxis. The outcome was 90-day mortality. We used multivariable Cox regression analyses to compare the effect. Hazard ratio (HR), 95% CIs, and P values were reported from the model. FINDINGS: From 2001 to 2012, a total of 3577 patients hospitalized for MACCEs (1997 received PPIs and 1580 received H2RBs) were admitted. The 90-day mortality was 23.7% (848/3577); it was 27% (540/1997) and 19.5% (308/1580) for PPIs and H2RBs users, respectively. The PPI group exhibited a greater 90­day mortality in comparison to the H2RBs group (relative risk = 1.17; P = 0.036), after conditioning on potential confounder. The results remained robust in propensity score matching, sensitivity analyses, and subgroup analyses. IMPLICATIONS: PPIs for stress ulcer prophylaxis were linked to an increased risk of in-hospital mortality than H2RBs in patients hospitalized for MACCEs. Further investigation of this association and validation of its clinical significance is needed.

Comprehensive Review on Bimolecular Fluorescence Complementation and Its Application in Deciphering Protein-Protein Interactions in Cell Signaling Pathways.

Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein-protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/ß-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways.

Pantoprazole and riluzole target H+/K+-ATPases and pH-sensitive K+ channels in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer type. PDAC is characterized by fibrotic, hypoxic, and presumably acidic tumor microenvironment (TME). Acidic TME is an important player in tumor development, progression, aggressiveness, and chemoresistance. The dysregulation of ductal ion transporters/channels might contribute to extracellular pH (pHe) acidification and PDAC progression. Our aim was to test whether H+/K+-ATPases and pH-sensitive K+ channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pHe conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H+/K+-ATPase inhibitor, alkalinized pHe. Second, we used FluoVolt to monitor the membrane voltage (Vm) and showed that riluzole hyperpolarized Vm, most likely by opening of pH-sensitive K+ channels such as TREK-1. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pHe conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co-targeting H+/K+-ATPases and pH-sensitive K+ channels by re-purposing of pantoprazole and riluzole could provide novel acidosis-targeted therapies of PDAC.

Chemical cross-linking and mass spectrometry enabled systems-level structural biology.

Structural information on protein-protein interactions (PPIs) is essential for improved understanding of regulatory interactome networks that confer various physiological and pathological responses. Additionally, maladaptive PPIs constitute desirable therapeutic targets due to inherently high disease state specificity. Recent advances in chemical cross-linking strategies coupled with mass spectrometry (XL-MS) have positioned XL-MS as a promising technology to not only elucidate the molecular architecture of individual protein assemblies, but also to characterize proteome-wide PPI networks. Moreover, quantitative in vivo XL-MS provides a new capability for the visualization of cellular interactome dynamics elicited by drug treatments, disease states, or aging effects. The emerging field of XL-MS based complexomics enables unique insights on protein moonlighting and protein complex remodeling. These techniques provide complimentary information necessary for in-depth structural interactome studies to better comprehend how PPIs mediate function in living systems.

Vonoprazan a novel potassium competitive acid blocker; another leap forward.

Introduction: The eradication rate of Helicobacter pylori (H. pylori) has decreased due to antibiotics resistance and inadequate acid suppression. Vonoprazan is a novel potassium-competitive acid blocker (P-CAB), which has a rapid and sustained acid inhibitory effect and may be more effective than conventional proton pump inhibitors (PPIs) in H. pylori eradication. Aim: to study the efficacy and safety of vonoprazan as a component of first-line H. pylori eradication treatment compared with conventional PPI-based therapy. Material and methods: This randomised (one to one) non-blinded study was conducted on 400 consecutive proven H. pylori infected patients, of whom 200 received vonoprazan-based triple therapy, while 200 patients received PPI-based triple therapy for 14 days. The study outcomes were evaluated as eradication rate and adverse events in both patient groups. Results: The eradication rate was 86% in the vonoprazan group and 74.5% in the PPI group. The vonoprazan eradication rate was significantly higher than that of PPIs (p = 0.004). There was no significant difference regarding adverse events between both patient groups. Conclusions: Vonoprazan-based therapy was more effective than PPI-based therapy as a first-line H. pylori eradication treatment. Vonoprazan was generally safe and well tolerated.

The Assessment of the Association of Proton Pump Inhibitor Usage with Chronic Kidney Disease Progression through a Process Mining Approach.

Previous studies have suggested an association between Proton Pump Inhibitors (PPIs) and the progression of chronic kidney disease (CKD). This study aims to assess the association between PPI use and CKD progression by analysing estimated glomerular filtration rate (eGFR) trajectories using a process mining approach. We conducted a retrospective cohort study from 1 January 2006 to 31 December 2011, utilising data from the Stockholm Creatinine Measurements (SCREAM). New users of PPIs and H2 blockers (H2Bs) with CKD (eGFR < 60) were identified using a new-user and active-comparator design. Process mining discovery is a technique that discovers patterns and sequences in events over time, making it suitable for studying longitudinal eGFR trajectories. We used this technique to construct eGFR trajectory models for both PPI and H2B users. Our analysis indicated that PPI users exhibited more complex and rapidly declining eGFR trajectories compared to H2B users, with a 75% increased risk (adjusted hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.49 to 2.06) of transitioning from moderate eGFR stage (G3) to more severe stages (G4 or G5). These findings suggest that PPI use is associated with an increased risk of CKD progression, demonstrating the utility of process mining for longitudinal analysis in epidemiology, leading to an improved understanding of disease progression.

Structural basis of the Integrator complex assembly and association with transcription factors.

Integrator is a multi-subunit protein complex responsible for premature transcription termination of coding and non-coding RNAs. This is achieved via two enzymatic activities, RNA endonuclease and protein phosphatase, acting on the promoter-proximally paused RNA polymerase Ⅱ (RNAPⅡ). Yet, it remains unclear how Integrator assembly and recruitment are regulated and what the functions of many of its core subunits are. Here, we report the structures of two human Integrator sub-complexes: INTS10/13/14/15 and INTS5/8/10/15, and an integrative model of the fully assembled Integrator bound to the RNAPⅡ paused elongating complex (PEC). An in silico protein-protein interaction screen of over 1,500 human transcription factors (TFs) identified ZNF655 as a direct interacting partner of INTS13 within the fully assembled Integrator. We propose a model wherein INTS13 acts as a platform for the recruitment of TFs that could modulate the stability of the Integrator's association at specific loci and regulate transcription attenuation of the target genes.

Vonoprazan causes symptomatic improvement in non-erosive gastroesophageal reflux disease: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of vonoprazan therapy as compared to conventional proton pump inhibitors (PPIs) or no vonoprazan for non-erosive esophagitis. METHODS: A thorough search was conducted across databases. The primary outcome was to determine the mean variance in the gastroesophageal reflux disease (GERD) score after vonoprazan treatment. Secondary outcomes comprised alterations in the scores for epigastric pain and post-prandial distress, the proportion of patients displaying improvement, and the occurrence of adverse events. Pooled mean differences and relative risks were determined utilizing random effects models. RESULTS: A total of 1,944 articles were screened and nine of them were included. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the GERD score [mean difference: -3.88 (95 % CI: -5.48, -2.28), p < 0.01, i2=95 %]. As compared to PPI or no vonoprazan therapy, vonoprazan treatment led to a significant reduction in the epigastric pain score [mean difference: -3.02 (95 % CI: -5.41, -0.63), p = 0.01, i2=75 %] and post-prandial distress score [mean difference: -2.82 (95 % CI: -3.51, -2.12), p < 0.01, i2=0 %] (all moderate GRADE evidence). Vonoprazan therapy was found to be safe. CONCLUSION: Treatment with vonoprazan could significantly improve symptoms in patients with non-erosive esophagitis or non-erosive GERD.

A Case of Severe Proton Pump Inhibitor-Induced Hypomagnesemia Refractory to Continuous Oral and Intravenous Magnesium Replenishment.

Proton pump inhibitors (PPIs) are frequently used medications to treat a wide variety of gastrointestinal conditions. By irreversibly inhibiting the hydrogen-potassium ATPase pump, they remarkably reduce gastric acid secretion. However, chronic PPI intake can result in serious complications, including severe hypomagnesemia. The following case report presents a severe case of refractory PPI-induced hypomagnesemia (PPIH), resistant to continuous oral and intravenous magnesium replacement, in a 70-year-old male patient, with a long history of PPI use due to persistent epigastric pain. Upon each of the 10 admissions to the hospital, he presented with severe signs and symptoms of hypomagnesemia, such as nausea, muscle fasciculation, diffuse cramps, weakness, neuromuscular irritability, and ECG disturbances, including non-specific T-wave abnormalities. In fact, PPIH has been reported for the first time in 2006. It is believed that the excessive, chronic intake of PPIs can disturb the normal functioning of the transient receptor potential melastatin 6/7 (TRPM 6/7), which is the main pathway of active intestinal magnesium absorption, leading to hypomagnesemia. PPIH is typically characterized by stubborn resistance to oral and intravenous magnesium replenishment but usually resolves after PPI withdrawal. Hence, despite being among the safest and most commonly prescribed drugs, PPI intake should be closely monitored when prolonged usage is planned. Additionally, continuous follow-up and regular assessment of serum magnesium levels are crucial to avoid the occurrence of PPIH and to prevent its potentially deleterious complications, including life-threatening arrhythmias.

A comprehensive review on potential drug-drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP-4 inhibitors.

A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitus is a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.