Dipeptidyl Peptidase Research Articles

Sodium glucose co-transporter 2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of Atrial Fibrillation in patients with type 2 diabetes mellitus: a meta-analysis

BackgroundSeveral studies showed higher risks of cardiovascular complications to have been observed in patients with type 2 diabetes mellitus (T2DM). Atrial fibrillation (AF) and atrial flutter have been more pronounced in patients with hyperglycemia. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are now considered as second-line treatment for patients with T2DM following inadequate glycemic control with first line agents. In this analysis, we aimed to compare the risk of AF in patients with T2DM who were treated with SGLT-2 inhibitors versus DPP-4 inhibitors.MethodsRelevant publications comparing AF in patients with T2DM treated by SGLT-2 inhibitors versus DPP-4 inhibitors were searched through electronic databases. AF was the clinical endpoint in this analysis. Revman 5.4 software was used to carry out this analysis. Risk ratios (RR) with 95% confidence intervals (CIs) were used to assess the outcome.ResultsEleven studies with a total number of 1,019,476 participants with T2DM were included in this analysis whereby 480,549 patients were assigned to SGLT-2 inhibitors and 538,927 patients were assigned to DPP-4 inhibitors. Result of this analysis showed SGLT-2 inhibitors to be associated with a significantly lower risk of AF compared to DPP-4 inhibitors in these patients with T2DM (RR: 0.57, 95% CI: 0.39 – 0.85; P = 0.006).ConclusionsBased on the result of this analysis, the risk of AF was significantly reduced with SGLT-2 inhibitors when compared to DPP-4 inhibitors in these patients with T2DM. This hypothesis should be confirmed in future larger studies.

Identification of CD209 as an Intervention Target for Type 2 Diabetes after COVID-19 Infection: Insights from Proteome-wide Mendelian Randomization.

Increasing evidence suggests that individuals infected with Coronavirus disease 2019 (COVID-19) are at a higher risk of developing type 2 diabetes (T2D) compared to those who are not infected. However, the mechanisms underlying this relationship remain poorly understood. In this study, we aimed to systematically evaluate the mediating roles of 3,283 plasma proteins in the link between COVID-19 susceptibility and T2D by conducting proteome-wide Mendelian randomization (MR) analyses. Reverse MR, validation in independent datasets, and colocalization analyses were conducted to verify the robustness of the MR results. Furthermore, mediation analysis was carried out to quantify the mediating effects. MR analyses between protein and T2D-related phenotypes were conducted to enhance the comprehension of potential mechanisms. Finally, the druggability of the identified proteins was evaluated. Four proteins causally associated with susceptibility to COVID-19 (ABO, CD209, CUZD1, and QXOS2) exhibited significant causal links with T2D. The protein CD209, which exhibited significant associations in validation and colocalization analyses, was identified as the causal mediating protein. Mediation analysis indicated that CD209 significantly mediated the total effect from COVID-19 susceptibility to T2D ( βindirect[95%CI]: 0.083[0.014-0.152], P=0.019). Further MR analyses revealed significant associations between CD209 and hemoglobin A1c, fasting glucose, fasting insulin, and waist-to-hip ratio. Evaluation of druggability demonstrated that CD209 can bind to Alpha-D-mannose and interact with 9 targets of T2D drugs including dipeptidyl peptidase 4 (DPP4). Our findings propose CD209 as a potential intervention target in individuals infected with COVID-19 to prevent T2D, providing novel insights into the pathophysiology linking COVID-19 and T2D.

Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics.

Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.

Antidiabetic Activity of Momordica charantia Extracts Through Incretin Pathway in Streptozotocin-Nicotinamide Induced Diabetic Rat Depends on Dose Differences

Background: This study addresses the increasing prevalence of type 2 Diabetes Mellitus (T2DM) and the need for alternative, cost-effective medications. The research problem focuses on the need to further study the dose effectiveness of Momordica charantia Extracts (MCE) on T2DM parameters, including Glucagon-Like Peptide 1 (GLP-1), Dipeptidyl Peptidase 4 (DPP-4), alpha glucosidase, glucosetransporter 5 (GLUT5), and pancreatic tissue histopathology. Methods: The methodology employed an experimental research design with 30 Wistar rats divided into six groups, each receiving different inductions and doses. Parameters were measured using Elisa, and histological analysis of pancreatic tissue was conducted using HE staining. Results: The Kruskal-Wallis test revealed significant differences in each group for the GLP-1 (p=0.003). However, the DPP4 test suggested a lack of significant difference in each group (p=0.192), and the GLUT5 test showed insignificant changes between each group (p=0.119). The ANOVA analysis on alpha-glucosidase revealed no statistically significant differences among the groups (p=0.202). Additionally, a qualitative examination of the histological analysis of pancreatic tissue indicated an improvement in the condition of the pancreatic tissue. Conclusion: MCE can increase GLP-1 levels, lower DPP-4, lower alpha-glucosidase, and raise GLUT5. However, there are no significant differences between other groups and the morphology of pancreatic tissue in rat model T2DM at a dose of 300 mg/kg.

Diverse autoinhibitory mechanisms of FIIND-containing proteins: Insight into regulation of NLRP1 and CARD8 inflammasome.

Function-to-find domain (FIIND)-containing proteins, including NLRP1 and CARD8, are vital components of the inflammasome signaling pathway, critical for the innate immune response. These proteins exist in various forms due to autoproteolysis within the FIIND domain, resulting in full-length (FL), cleaved N-terminal (NT), and cleaved C-terminal (CT) peptides, which form autoinhibitory complexes in the steady state. However, the detailed mechanism remains elusive. Here, we found that both NLRP1 paralogs and CARD8 form two conserved autoinhibitory complexes involving NT-CT interactions and FL-CT interactions, but with distinct mechanisms. Specifically, the Linker3 region located between LRR and FIIND in murine NLRP1b (mNLRP1b) plays an essential role in forming the NT-CT autoinhibitory complexes, while the ZU5 of rat NLRP1 (rNLRP1) and CARD8 mediates their NT-CT interaction. In addition, we explored the involvement of the cellular protease dipeptidyl peptidases 9 (DPP9) in these complexes, revealing differential interactions and the significance of domain structure. Besides the FL-DPP9-CT complex, DPP9 interacts with NTs of mNLRP1b, rNLRP1, and CARD8 through their ZU5 subdomains, forming NT-DPP9-CT complex; however, DPP9 cannot bind to NTs of hNLRP1. Further functional assay indicated that although DPP9 is involved in the NT-CT complex of rodent NLRP1 and CARD8, it does not influence the inhibitory activity of NT on CT. Our study enhanced the understanding of the regulatory functions of FIIND-containing proteins in inflammasome autoinhibition and activation and underscored the complexity of their interactions within the immune response.

GLP-1RA Use and Thyroid Cancer Risk

The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) demands a better understanding of their association with thyroid cancer. To estimate the risk of incident thyroid cancer among adults with type 2 diabetes being treated with GLP-1RA vs other common glucose-lowering medications. This was a prespecified secondary analysis of a target trial emulation of a comparative effectiveness study using claims data for enrollees in commercial, Medicare Advantage, and Medicare fee-for-service plans across the US. Eligible participants were adults with type 2 diabetes at moderate risk for cardiovascular disease and without history of thyroid cancer who had newly filled prescriptions for GLP-1RA, sodium-glucose cotransporter 2 inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP4i), or sulfonylurea from January 1, 2014, to December 31, 2021. Data were analyzed February 1 to October 31, 2024. Overall and piecewise (<1, 1-2, and ≥2 years since treatment initiation) hazard ratios (HRs) for thyroid cancer with use of GLP-1RA vs the other 3 drug classes were estimated using inverse propensity score weighted Cox proportional hazards models. Modified intention-to-treat (mITT) (primary) and as-treated (sensitivity) analyses were performed. Of 351 913 patients (mean [SD] age, 65.3 [8.5] years; 173 391 [49.3%] females and 178 522 [50.7%] males), 41 112 started treatment with GLP-1RA; 76 093, with DPP4i; 43 499, with SGLT2i; and 191 209, with sulfonylurea therapy. The numbers of patients diagnosed with thyroid cancer were 69 (0.17%) in the GLP-1RA group, 172 (0.23%) in the DPP4i group, 72 (0.17%) in the SGLT2i group, and 381 (0.20%) in the sulfonylurea group. In the mITT analysis, GLP-1RA initiation was not significantly associated with increased overall risk for thyroid cancer compared to the other 3 diabetes drugs (HR, 1.24; 95% CI, 0.88-1.76). However, the risk for thyroid cancer was significantly higher within the first year after GLP-1RA initiation (HR, 1.85; 95% CI, 1.11-3.08) and was amplified in the overall as-treated analysis that censored patients when therapy was discontinued or another medication was added (HR, 2.07; 95% CI, 1.10-3.95). This secondary analysis of a target trial emulation of a comparative effectiveness study found that despite the low absolute risk of thyroid cancer among patients receiving GLP-1RA therapy, there was an increased risk of new thyroid cancer diagnoses within the first year of GLP-1RA initiation compared to 3 other diabetes drugs. This finding may have been due to enhanced early detection; therefore, further research is necessary to understand the underlying causes of this association.

Bioactive potential and storage behavior of low molecular mass peptides in Pilsner and IPA style craft beers

Beer, one of the most widely consumed alcoholic beverages globally, is typically produced from barley and hops, and contains carbohydrates, proteins, vitamins, minerals, ethanol, and bioactive phytochemicals such as phenolic compounds. However, the knowledge of protein content, particularly bioactive peptides in beer, remains limited. Given that beer production involves raw materials rich in both proteins and proteolytic enzymes, which may remain active throughout the product’s shelf life, beer holds potential as a source of bioactive peptides. This study aimed to investigate the presence of bioactive di- and tripeptides in craft beer samples from Pilsner and IPA styles, after 3 or 6 months of storage. LC-MS/MS analysis was performed using the 46 Da neutral loss method and collision-induced dissociation, followed by peptide bioactivity screening through the BIOPEP database. Twelve di- and tripeptides, with masses ranging from 177 to 329 (m/z), were identified, exhibiting potential bioactivities such as dipeptidyl peptidase IV and III inhibition, ACE inhibition, and antioxidative properties. These activities are associated with reduced risk of high blood pressure and metabolic syndrome. After 3 months of storage, peptide intensity decreased in Pilsner samples but increased in IPA samples. Pilsner beers, typically clear due to added chill-proofing proteases, showed reduced peptide intensity over time, whereas IPA, which often remains hazy and lacks such enzymes, exhibited increased peptide levels. These findings suggest that Pilsner beers may benefit from quicker consumption, while IPA may be better suited for longer storage to maximize bioactive peptide intake.

Comparison of Clinical Outcomes Between Two Types of Dipeptidyl Peptidase-4 Inhibitors in Posttransplant Diabetes Mellitus in Kidney Transplantation Recipients: A Nationwide Population-Based Cohort Study in Korea.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are antidiabetic drugs known for their minimal side effects and limited drug interaction witih immunosuppressants, making them suitable for patients with diabetes and kidney transplant recipients. However, there is limited real-world information regarding the use of DPP-4 inhibitors in patients with post transplant diabetes mellitus (PTDM). We performed a retrospective observational cohort study of 13,828 kidney transplant recipients form Janary 1, 2002, through December 21, 2018, using the Korean National Health Information Database. We extracted PTDM patients, and divided the patients into 2 groups baased on whether they received DPP4-inhibitor which needs dose adjustement (group A) or not (Group B) according to estimaged glomerular filtration rate. Out of 3154 patients who developed PTDM after transplantation, 738 patients prescribed DPP-4 inhibitors. Among these, 490 patients prescribed Group B DPP-4 inhibitors and 238 patients prescribed Group A DPP-4 inhibitors. Multivariate-adjusted Cox regression analysis showed that compared Group B, Group A DPP-4 inhibitors was associated with higher incidence rate of genital tract infection (hazard ratio (HR) 1.87, 95% Confidence Interval (CI) 1.18-2.99), and emergency department visit (HR 3.12, 95% CI 1.89-5.16). However, there was no significantly difference in death (any cause), admission, graft failure, infection, or hypoglycemia between the 2 groups. In patients with PTDM, some kinds of DPP-4 inhibitors, which need dose adjustment according to renal function, were associated with an increased rate of emergency department visit and genital tract infection.

Association between use of sodium-glucose co-transporter-2 inhibitor and the risk of incident dementia: a population-based cohort study

ObjectivesTo assess the association between sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use and the risk of incident dementia compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) use among individuals with type 2 diabetes.DesignA population-based...

Mapping the effectiveness and risks of GLP-1 receptor agonists.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium-glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.

Evolution and therapeutic potential of glucagon-like peptide 2 analogs.

Glucagon-like peptide 2 (GLP-2) is a proglucagon-derived peptide released by intestinal endocrine cells. However, its therapeutic potential is limited by rapid inactivation via dipeptidyl peptidase-IV. The elucidation of three-dimensional structures of G-protein-coupled receptors, including GLP-2 receptor, has facilitated the rational design of novel peptide therapeutics. Recent studies have explored various structural modifications based on the structure of GLP-2, such as amino acid substitution, lipidation, and fusion with proteins, to extend the half-life of GLP-2 and enhance its biological activity. One promising avenue involves the development of multifunctional molecules targeting multiple pharmacological systems to boost therapeutic efficacy. This paper reviews the recent advancements in understanding GLP-2, including its physiological roles and structure-activity relationships, and evaluates the development prospects of GLP-2 analogs.

Epithelium-derived exosomal dipeptidyl peptidase-4 involved in arecoline-induced oral submucous fibrosis.

Dipeptidyl peptidase-4 is known to be involved in the progression of several fibrogenic diseases, but its association with oral submucous fibrosis remains unclear. This study aims to ascertain whether dipeptidyl peptidase-4 plays a role in the pathogenesis of arecoline-induced oral submucous fibrosis. We assessed the expression of dipeptidyl peptidase-4 in arecoline-treated epithelial cells and the exosomes derived from cells. We cocultured the fibroblast and exosomes derived from epithelium cells and assessed fibrogenic activity by measuring collagen secretion, α-SMA expression, and gel contraction capability. An animal study was conducted to confirm the fibrogenic activity of exosomes derived from arecoline-treated epithelial cells. Additionally, we employed a dipeptidyl peptidase-4 inhibitor to assess its efficacy in mitigating fibrogenesis. Following arecoline treatment, an increase dipeptidyl peptidase-4 expression was observed in exosomes from the treated epithelium cells. When these exosomes cocultured with fibroblast, fibrogenic gene α-SMA was upregulated, increased collagen secretion, and enhanced gel contraction capability. In a mouse model, the administration of arecoline-treated epithelium-derived exosomes induced oral submucous fibrosis phenotype, characterized by a reduction in incisal distance and epithelial atrophy. These findings offer valuable insights into clinical strategies for combating oral fibrotic disease and contribute to the foundation of future research in this field.

Current and novel biomarkers in cardiogenic shock.

Cardiogenic shock (CS) carries a 30-50% in-hospital mortality rate, with little improvement in outcomes in the last decade. Challenges in improving outcomes are closely linked to the frequent late presentation or diagnosis of CS where the 'point of no return' has often passed, leading to haemodynamic dysregulation, progressive myocardial depression, hypotension, and a downward spiral of hypoperfusion, organ dysfunction and decreasing myocardial function, driven by inflammation and metabolic derangements. Novel therapeutic interventions may have varying efficacy depending on the type and stage of shock in which they are applied. Biomarkers that aid prediction and early detection of CS, provide early signs of organ dysfunction and define prognosis could help optimize management. Temporal change in such biomarkers, particularly in response to pharmacological interventions and/or mechanical circulatory support, can guide management and predict outcome. Several novel biomarkers enhance the prediction of mortality in CS, compared to conventional parameters such as lactate, with some, such as adrenomedullin and circulating dipeptidyl peptidase 3, also able to predict the development of CS. Some biomarkers reflect systemic inflammation (e.g. interleukin-6, angiopoietin 2, fibroblast growth factor 23 and suppressor of tumorigenicity 2) and are not specific to CS, yet inform on the activation of important pathways involved in the downward shock spiral. Other biomarkers signal end-organ hypoperfusion and could guide targeted interventions, while some may serve as novel therapeutic targets. We critically review current and novel biomarkers that guide prediction, detection, and prognostication in CS. Future use of biomarkers may help improve management in these high-risk patients.

DPP4, a potential tumor biomarker, and tumor therapeutic target: review.

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.

A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment.

Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose. Based on the optimization of renal function-dependent parameters, the model was extrapolated to different stages renal impairment patients. Ultimately our model adequately describes the pharmacokinetics of alogliptin, the progression of DPP-4 inhibition over time and the dynamics of the glucose control system components. The extrapolation results endorse the dose adjustment regimen of 12.5mg once daily for moderate patients and 6.25mg once daily for severe and ESRD patients, while providing additional reflections and insights. In clinical practice, our model could provide additional information on the in vivo fate of DPP4 inhibitors and key regulators of the glucose control system.

Bioinformatic Analysis for Exploring Target Genes and Molecular Mechanisms of Cadmium-Induced Nonalcoholic Fatty Liver Disease and Targeted Drug Prediction.

Cadmium (Cd) is a widely available metal that has been found to have a role in causing nonalcoholic fatty liver disease (NAFLD). However, the detailed toxicological targets and mechanisms by which Cd causes NAFLD are unknown. Therefore, the present work aims to reveal the main targets of action, cellular processes, and molecular pathways by which cadmium causes NAFLD. As shown in the bioinformatics analysis, there were 74 main targets of action for cadmium-induced NAFLD, hemopoietic cell kinase (HCK), EPH receptor A2 (EPHA2), MYC proto-oncogene (MYC), lysyl oxidase (LOX), dipeptidyl peptidase 7 (DPP7), nuclear factor erythroid 2-related factor 2 (NFE2L2), dual specificity phosphatase 6 (DUSP6), CD2 cytoplasmic tail binding protein 2 (CD2BP2), notch receptor 3 (NOTCH3), and phospholipase A2 group IVA (PLA2G4A) were screened as core genes. Testing these core genes in other databases, three differentially expressed genes, HCK, MYC, and DUSP6 were verified and used as targets for drug prediction in DsigDB; decitabine and retinoic acid were screened as potential therapeutic drugs for NAFLD based on the p-value and the combined score. The results of molecular docking showed that the predicted drugs can bind well to the core targets. In conclusion, cadmium is associated with NAFLD; the identified cadmium-toxicity targets, HCK, MYC, and DUSP6, may serve as biomarkers for the diagnosis of NAFLD and predicted drugs, decitabine and retinoic acid may have a potential role in the treatment of NAFLD.

Risk of insulin initiation with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: A real-world claims database study in Japan.

Insulin therapy is a cornerstone in type 2 diabetes mellitus (T2DM) management, but its use is associated with several barriers, including hypoglycaemia, fear of injections and high costs. We compared the risk of insulin initiation and other treatment intensification between patients with T2DM newly treated with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus those newly treated with a dipeptidyl peptidase-4 inhibitor (DPP4i). This Japanese retrospective cohort study was conducted between 1 January 2015 and 31 March 2023 using the JMDC Claims Database. Patients with T2DM newly treated with an SGLT2i or a DPP4i were matched 1:1 using propensity score (n = 18 488 each). Incidence rates (IR) of insulin initiation, other antidiabetic drugs (OAD) and antihypertensive drugs added onto baseline treatment were calculated for each treatment group. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model. The IR of insulin initiation was 0.95 and 2.12 per 1000 person-years in the SGLT2i and DPP4i groups, respectively, with significantly lower risk in the SGLT2i group than in the DPP4i group (HR 0.46, 95% CI: 0.28-0.74, p = 0.001). The risks of OAD (HR 0.66, 95% CI: 0.64-0.69, p < 0.001) and antihypertensive drugs (HR 0.90, 95% CI: 0.85-0.95, p < 0.001) added onto baseline treatment were lower in the SGLT2i group than in the DPP4i group. The risk of insulin initiation was lower in patients with T2DM newly treated with an SGLT2i than in those newly treated with a DPP4i. SGLT2i may reduce or delay the need for insulin therapy.

Effects of Novel Antidiabetic Agents on Contrast-Associated Acute Kidney Injury in Diabetic Patients Undergoing Percutaneous Coronary Intervention.

Contrast-associated acute kidney injury (CA-AKI) remains a serious complication after percutaneous coronary revascularization (PCI), with limited effective preventive strategies especially for diabetic patients. This study aimed to assess the effects of novel antidiabetic agents (NAD), i.e., glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose transporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP4i), on the occurrence of this outcome in diabetic patients undergoing PCI. We enrolled 293 consecutive diabetic patients receiving NAD at the time of PCI (NAD group) and paired them with 293 diabetic individuals undergoing revascularization who were not on NAD (no-NAD group), matched according to age and sex. CA-AKI was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dl or >50% from baseline within 48-72 hours after contrast exposure. A propensity score-adjusted logistic regression analysis was performed to account for potential selection bias. NAD treatment was associated with a significantly reduced incidence of CA-AKI than standard glucose-lowering therapies (4.1 vs. 8.5%, p=0.023). Furthermore, patients using SGLT2i and GLP-1RAs exhibited a lower incidence of CA-AKI compared to those taking DPP4i. Both multivariate and propensity-score-adjusted regression analyses identified NAD therapy as an independent predictor of CA-AKI (OR 0.45, 95% CI 0.22-0.98, p=0.040 and OR 0.48, 95% CI 0.23-0.98, p=0.045). In conclusion, this study is the first to explore the potential benefit of all three NAD classes on CA-AKI incidence. The use of these agents is associated with a lower incidence of renal damage in diabetic patients undergoing PCI, with the greatest benefit observed with SGLT2i and GLP-1RAs use.

Lifestyle and Pharmacologic Approaches to Prevention of MASLD-related HCC.

Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns, e.g., high consumption of vegetables, whole grains, fish, and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate anti-diabetic therapy for individuals with liver disease and diabetes may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RA), aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time given a dearth of data defining their risk-benefit ratio.

Cardiovascular risk associated with glucagon-like peptide-1 receptor agonists versus other conventional glucose-lowering drugs in patients with type-2 diabetes: protocol for a nationwide observational comparative study in routine care

IntroductionSeveral cardiovascular outcome trials have been conducted to assess the cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on cardiorenal outcomes in patients with type-2 diabetes (T2D). However,...