Dipeptidyl Peptidase-4 Inhibitors Research Articles

Comparative Outcomes of Glucagon-Like Peptide-1 Receptor Agonists to Dipeptidyl Peptidase 4 Inhibitors in Patients With Heart Failure and Type 2 Diabetes.

Clinical trials showed that glucagon-like peptide-1 receptor agonist (GLP1-RA) significantly improved the control of diabetes and reduced body weight compared with dipeptidyl peptidase 4 inhibitor (DPP-4i). However, it is unclear whether GLP1-RA is effective compared with DPP-4i in patients with heart failure (HF) with type 2 diabetes (T2D). The purpose of this study was to evaluate the risk of GLP1-RA compared with DPP-4i in all-cause death and hospitalization in patients with HF and T2D. This multicenter retrospective observational study using TriNetX, a global health care data and analytics platform, included patients with HF and T2D who had received GLP1-RA or DPP-4i from January 1, 2018, to December 31, 2022. Primary outcome was 12-month incidence of all-cause death. Secondary outcome was hospitalization. We used odds ratios (ORs) and 95% CIs to evaluate outcome measures. Among 1 005 097 patients with HF and T2D, 57 965 initiated GLP1-RA and 77 098 initiated DPP-4i. After propensity score matching, the number of participants in both the GLP1-RA group and the DPP-4i group was 36 557. The proportion of 12-month incidence of all-cause death was lower in the GLP1-RA group than in the DPP-4i group (5.9% [2140/36 557] versus 8.5% [3103/36 557]; OR, 0.67 [95% CI, 0.63-0.71]).The proportion of 12-month incidence of hospitalization was also lower in the GLP1-RA group than in the DPP-4i group (42.3% [15 455/36 557] versus 48.5% [17 733/36 557]; OR, 0.78 [95% CI, 0.76-0.80]). Use of GLP1-RA for patients with HF and T2D was associated with reduced 12-month incidence of all-cause death and hospitalization compared with DPP-4i.

Drug Repositioning and Repurposing for Disease-Modifying Effects in Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and is characterized by progressive dopaminergic and non-dopaminergic neuronal loss and the presence of Lewy bodies, which are primarily composed of aggregated α-synuclein. Despite advancements in symptomatic therapies, such as dopamine replacement and deep brain stimulation, no disease-modifying therapies (DMTs) have been identified to slow or arrest neurodegeneration in PD. Challenges in DMT development include disease heterogeneity, the absence of reliable biomarkers, and the multifaceted pathophysiology of PD, encompassing neuroinflammation, mitochondrial dysfunction, lysosomal impairment, and oxidative stress. Drug repositioning and repurposing strategies using existing drugs for new therapeutic applications offer a promising approach to accelerate the development of DMTs for PD. These strategies minimize time, cost, and risk by using compounds with established safety profiles. Prominent candidates include glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, ambroxol, calcium channel blockers, statins, iron-chelating agents, c-Abl inhibitors, and memantine. Although preclinical and early clinical studies have demonstrated encouraging results, numerous phase III trials have yielded unfavorable outcomes, elucidating the complexity of PD pathophysiology and the need for innovative trial designs. This review evaluates the potential of prioritized repurposed drugs for PD, focusing on their mechanisms, preclinical evidence, and clinical trial outcomes, and highlights the ongoing challenges and opportunities in this field.

Glucagon-Like Peptide 1 Receptor Agonists and Venous Thromboembolism in Type 2 Diabetes: A Target Trial Emulation.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are anti-diabetes agents recently approved for weight loss. Obesity is an established risk factor for venous thromboembolism (VTE). Moreover, preclinical studies have shown that GLP1-RA may attenuate thromboxaneinduced platelet activation. Therefore, we hypothesized that GLP1-RA use may reduce the risk of VTE. We performed a target trial emulation using a population-based database of electronic health records to evaluate whether GLP1-RA use is associated with a reduction in VTE in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidas e-4 inhibitors (DPP4i). Patients who were newly initiated on GLP1-RA were propensity scorematched to patients who were newly initiated on DPP4i. We evaluated the primary outcome, composite VTE, identified using ICD-10 codes, within 12 months of the initiation of GLP1-RA or DPP4i. The study cohort comprised 540,258 patients with 270,129 individuals receiving either GLP1-RA or DPP4i. Over 12 months of follow-up, patients who received GLP1-RA had a lower incidence of VTE compared with patients who received DPP4i (6.1 vs. 7.6 events per 1000 patient-years, hazard ratio [HR], 0.78 [95% CI: 0.73-0.83]). This was similar for PE (2.9 vs. 3.8 events per 1000 patient-years, HR, 0.74 [95% CI: 0.68-0.82]) and DVT (3.9 vs. 4.7 events per 1000 patient-years, HR, 0.81 [95% CI: 0.75-0.88]). In this propensity scorematched, target trial emulation study, patients with T2DM who received a GLP1-RA had a lower risk of VTE at one year compared with patients who received DPP4i.

Diabetic Ketoacidosis and the Use of New Hypoglycemic Groups: Real-World Evidence Utilizing the Food and Drug Administration Adverse Event Reporting System

Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors. Methods: DKA reports from Q1 2019 to Q3 2024 were retrieved from the FDA Adverse Event Reporting System (FAERS). Associations between primary exposure and outcomes were ascertained using four key metrics: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Component (IC). Results: SGLT2 inhibitors exhibited the higher DKA risk in 2019–2021 (ROR: 314.86 [95% CI 301.76–328.53], PRR of 245.69 [95% CI 235.47- 256.36], IC of 6.90, and EBGM of 120), declining in 2022–2024. GLP-1 receptor agonists showed an ROR increase from 2.88 [95% CI 2.56–3.25] in 2019–2021 to 4.64 [95% CI 4.06–5.29] in 2022–2023, slightly declining to 3.95 [95% CI 3.27–4.74] in 2024. DPP-4 inhibitors exhibited a steady ROR rise from 6.81 [95% CI 5.52–8.40] in 2019–2021 to 8.57 [95% CI 6.24–11.76] in 2022–2023 and further to 11.02 [95% CI 6.71–18.10] in 2024. PRR, EBGM, and IC values followed similar trends. The age groups 41–60 and 61–91 years were the most affected, with hospitalization at its highest rate for DPP4-inhibitors in Q1-Q3 of 2024. Hospitalizations were also observed with GLP-1 receptor agonists and SGLT2 inhibitors. Life-threatening events and fatalities were also reported, with physicians contributing to most reports. Conclusions: DKA signals were observed for all three drug classes, particularly among elderly patients, highlighting the need for careful monitoring, especially during periods of illness or stress. However, the risk was higher in the SGLT2 inhibitor group than in the other groups.

The Dipeptidyl Peptidase-4 Inhibitor Saxagliptin as a Candidate Treatment for Disorders of Consciousness: A Deep Learning and Retrospective Clinical Analysis.

Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes. To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury. Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage. Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.

Effect of SGLT2i on kidney outcomes of individuals with type 2 diabetes according to body mass index: nationwide cohort study.

To investigate the clinical significance of the modification of the kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors by baseline body mass index (BMI). We included individuals with SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP4) inhibitors newly prescribed for type 2 diabetes using a nationwide epidemiological cohort and performed propensity score matching (1:2). The primary outcome was the annual eGFR decline, assessed using a linear mixed-effects model, compared between individuals with SGLT2 inhibitors and DPP4 inhibitors. We investigated the interaction effect of BMI at the time of prescription using a three-knot restricted cubic spline model. We analysed 2165 individuals with SGLT2 inhibitor prescriptions and 4330 individuals with DPP4 inhibitor prescriptions. Overall, the annual decline in eGFR was less pronounced in the group treated with SGLT2 inhibitors than in those treated with DPP4 inhibitors (-1.34mL/min/1.73 m2 vs. -1.49mL/min/1.73 m2). The advantage of SGLT2 inhibitors in mitigating eGFR decline was augmented in the individuals with higher BMI (P-value for interaction 0.0017). Furthermore, even upon adjusting the definition of outcomes to encompass a 30 or 40% reduction in eGFR, the potential advantages of SGLT2 inhibitors over DPP4 inhibitors persisted, with a trend of augmented effects with higher BMI. This interaction effect was evident in the individuals with preserved kidney function. Our nationwide epidemiological study substantiated the improved kidney outcomes in the SGLT2 inhibitor users compared with the DPP4 inhibitor users across a wide range of BMI, which was pronounced for individuals with higher BMI.

Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Hemoglobin A1c (HbA1c) and MACEs. Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.

Identification and Characterization of Novel Bioactive Peptide From Red Seaweed (Pyropia vietnamensis) Proteins

Pyropia vietnamensis is one of the most abundant seaweeds in the Indo-Pacific region. This study aimed to perform an in silico evaluation of P. vietnamensis proteins as potential precursors of bioactive peptides and to determine the novel peptide in terms of its half maximal inhibitory concentration (IC50) and the stability under controlled laboratory environment (in vitro) towards the dominant biological activity. The proteomic profiles of P. vietnamensis proteins were determined using LC-MS/MS analysis. Next, five proteins were chosen and employed for in silico analysis using the BIOPEP-UWM database. The in vitro characterizations of novel peptide were carried out using a dipeptidyl peptidase-IV (DPP-IV) inhibitor screening assay kit. In silico analysis revealed that DPP-IV and angiotensin-converting enzyme (ACE) inhibitors were the most potential bioactive peptides in P. vietnamensis proteins. Calpain 2, papain, pepsin (pH>2), and stem bromelain were predicted as the enzymes with the most potential to produce DPP-IV and ACE inhibitors. The novel peptides predicted were CFA, ACF, RFPS, DEWG, NYCL, CVPR, and DACF. The synthesized CVPR with an IC50 of 0.66 mg/ml exhibited stability at pH 3-7, 30-50 °C, and resisted gastrointestinal digestion. This study revealed P. vietnamensis proteins could offer health benefits due to the therapeutic potential with sustainable industrial applications on functional foods, nutraceuticals, and pharmaceuticals.

Dipeptidyl peptidase 4 is a cofactor for porcine epidemic diarrhea virus infection.

Porcine epidemic diarrhea virus (PEDV) is a member of the genus Alphacoronavirus in the family Coronaviridae, which has a mortality rate of up to 100 % in neonatal piglets and causes huge economic losses to the pig industry. The target cells of PEDV infection are porcine small intestinal epithelial cells, and the mechanism of PEDV invasion remains unclear. Our study found that dipeptidyl peptidase 4 (DPP4) acts as a cofactor for PEDV infection by promoting PEDV invasion and replication. Firstly, we mapped the expression profile of DPP4 in different tissues of 7-day-old piglets and found that DPP4 was highly expressed in the liver, lung, kidney, duodenum, jejunum, and ileum tissues of piglets. In addition, the immunohistochemical results showed that DPP4 was mainly distributed at the apical of intestinal villous epithelial cells in the jejunum of piglets. Further studies revealed that DPP4 expression was significantly lower in PEDV-infected porcine jejunal tissues and IPEC-J2 cells than in uninfected controls. PEDV invasion and replication could be inhibited by DPP4 inhibitor and specific antibody. Moreover, DPP4 knockout was able to significantly inhibit PEDV infection. Then, we found that endogenous DPP4 interacted with PEDV, and that preincubation of PEDV with endogenous DPP4 reduced viral infection. Finally, we predicted the docking of DPP4 and PEDV-S1-RBD proteins in silico, showing a strong binding tendency. Taken together, our study supports the hypothesis that DPP4 is a cofactor for PEDV infection.

A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers.

Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients. The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design. A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients. This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer.

Suicide and suicide attempt in users of GLP-1 receptor agonists: a nationwide case-time-control study.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are extensively evaluated for the risk of suicidal behaviors or ideation; the influence of psychiatric history or obesity on this potential effect remains to be investigated. Therefore, we aimed to assess the association between GLP-1 RA and suicide or suicide attempt, considering these factors. Patients ≥18y who died by suicide or were hospitalized for suicide attempt (2013-2021) with at least one GLP-1 RA dispensing within the 180 preceding days were selected from the French National Health Data System (SNDS). A case-time-control design compared, for each patient, GLP-1 RA exposure in the 30 days preceding the outcome (composite of suicide or suicide attempt) to three earlier 30-day reference periods. Potential exposure trend bias was controlled using up to five time-controls matched on age, sex, psychiatric history, obesity, calendar time. Analyses were adjusted for time-varying confounders. Finally dipeptidyl peptidase-4 (DPP-4) inhibitors were studied as negative controls for potential biases. This study included 1102 cases and 5494 controls. Mean case age was 57.4 years (SD 11.4); 44.6% were male, 67.6% had a recent psychiatric history and 51.3% had obesity. GLP-1 RA use was not associated with an increased risk of suicide or suicide attempt (OR, 0.62; 95% CI, 0.51-0.75), with consistent results for DPP-4 inhibitors (0.75; 0.67-0.84). Results obtained according to recent psychiatric history and obesity were comparable. This large nationwide case-time-control study provides reassurance about the short-term psychiatric safety of GLP-1 RA, showing no specific risk for patients with psychiatric disorders or obesity. French Medicines Agency.

Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia

Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia

Impact of GLP-1 Receptor Agonists on Alcohol-Related Liver Disease Development and Progression in Alcohol Use Disorder.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in reducing alcohol consumption, but their impact on clinical outcomes in patients with alcohol use disorder (AUD) remains unclear. We investigated the association between GLP-1RAs and the development and progression of alcohol-related liver disease (ArLD) in patients with AUD. Using the TriNetX Research Network, we conducted two retrospective cohort studies comparing GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with type 2 diabetes. The first cohort included patients with AUD but without ArLD (n = 7132 after propensity score matching), while the second comprised patients with established ArLD (n = 1896 after matching). Primary outcomes were incident ArLD in the AUD cohort and hepatic decompensation in the ArLD cohort. In the AUD cohort (median follow-up: 63.2 months), GLP-1RA users showed significantly lower risks of developing ArLD compared to DPP-4i users (incidence rate: 6.0 vs. 8.7 per 1000 person-years; HR: 0.62, 95% CI: 0.44-0.87, p = 0.006). GLP-1RAs were also associated with reduced risks of all-cause mortality (HR: 0.53, p < 0.001). In the ArLD cohort (median follow-up: 28.2 months), GLP-1RA users demonstrated lower risks of hepatic decompensation (incidence rate: 39.5 vs. 51.4 per 1000 person-years; HR: 0.66, 95% CI: 0.51-0.85, p = 0.001) and all-cause mortality (HR: 0.53, p < 0.001) compared to DPP-4i users. GLP-1RAs were associated with reduced risks of developing and progressing ArLD in patients with AUD, suggesting potential therapeutic benefits in this population.

In-silico discovery of Dipeptidyl Peptidase-4 inhibitors from African medicinal plants: Molecular docking, ADMET, dynamics simulation, and MM-GBSA analyses

In-silico discovery of Dipeptidyl Peptidase-4 inhibitors from African medicinal plants: Molecular docking, ADMET, dynamics simulation, and MM-GBSA analyses

In Silico Screening of Laminaria japonica Ligands as Potential Inhibitors of DPP-4 for Type 2 Diabetes Treatment

In Silico Screening of Laminaria japonica Ligands as Potential Inhibitors of DPP-4 for Type 2 Diabetes Treatment

Rapid screening and identification of novel dipeptidyl peptidase IV inhibitory peptides from buffalo milk.

Peptidomics combined with molecular docking is an effective alternative method for rapid screening of novel bioactive peptides in food. Buffalo milk as a potential source of dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides has been less studied. Peptidomics and molecular docking methods were employed to rapidly screen new DPP-IV inhibitory peptides from buffalo milk. The screened DPP-IV inhibitory peptides were further verified using an in vitro inhibition assay and a Caco-2 cell assay. The DPP-IV inhibition rate of buffalo milk was increased from 73.40 ± 6.01% to 97.23 ± 3.18% in an in vitro digestion assay, suggesting that buffalo milk could be a promising source of DPP-IV inhibitory peptides. Subsequently, two novel peptides (GPFPIIV and FPQYL) with potential DPP-IV inhibitory activity were screened using peptidomics, molecular docking and an in vitro inhibitory assay. The IC50 values for GPFPIIV and FPQYL were 0.2998 ± 0.03 and 0.1407 ± 0.01 mg mL-1, respectively. During simulated gastrointestinal digestion in vitro, FPQYL had an excellent digestive stability of 92.13 ± 1.03%, whereas that of GPFPIIV was 59.52 ± 2.56%. In addition, GPFPIIV and FPQYL (1.00 mg mL-1) showed significant DPP-IV inhibitory effects in a Caco-2 cell assay, with the inhibition rate increasing to 32% and 36%, respectively. In summary, two new DPP-IV inhibitory peptides were screened from buffalo milk through a combination of peptidomics and molecular docking, both of which exhibited significant DPP-IV inhibitory activities. The identified peptides, GPFPIIV and FPQYL, have promising applications in diabetes management. © 2025 Society of Chemical Industry.

Clinical effectiveness and cost-effectiveness of first-line early combination of dipeptidyl peptidase 4 inhibitors and metformin in patients with type 2 diabetes in Taiwan: A modelling study.

Early dipeptidyl peptidase-4 inhibitors and metformin (DPP4i-Met) combination has been shown to extend the time to treatment failure and provide better glycaemic control for newly diagnosed type 2 diabetes (T2D) patients; however, the long-term clinical and economic outcomes of early DPP4i-Met combination remain unknown. We seek to assess the comparative long-term clinical and cost-effectiveness of DPP4i-Met versus Met for treatment-naïve T2D patients with inadequately controlled HbA1c (i.e., ≥8.5%). The IQVIA CORE Diabetes Model was used to simulate the quality-adjusted life years (QALYs) and healthcare costs over a lifetime from Taiwan's National Health Insurance Administration's perspective, with both QALYs and costs discounted at 3% annually. Model inputs were taken from the analyses of Taiwanese or Asian populations. Primary outcomes included the number needed to treat (NNT) to prevent one case of a clinical event and the incremental cost-effectiveness ratios (ICERs). Costs are presented in 2023 US dollars. Over 40 years of projection, Met-DPP4i-treated patients had fewer complications than those using Met alone (e.g., lowering the incidence of stroke by 2.21% [2.68, 1.74]). The NNT using DPP4i-Met versus Met alone to prevent one case of stroke, microalbuminuria, neuropathy and background retinopathy was 45, 135, 65 and 182, respectively. Such long-term benefits in reducing costly complications offset the higher treatment cost of DDP4i-Met versus Met ($5796 vs. $5484/person). As a result, using DPP4i-Met versus Met yielded 0.086 QALYs gained and savings of $489 for overall treatment-naïve T2D patients and 0.064 QALYs gained and savings of $714 for young-onset T2D patients. Early DPP4i-Met provides long-term clinical and economic benefits compared to Met alone for newly diagnosed T2D patients, including those with young-onset T2D.

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.

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.

Unraveling the Mystery: COVID-19 and Diabetic Complications - A Journey from Pathophysiology to Treatment.

The connection between COVID-19 and DM unveils a multifaceted interplay that significantly impacts disease severity and management strategies. Initial studies reveal that people with DM had higher severity rates of COVID-19 due to the infection by SARS-CoV-2. The virus solely induces hyperglycemia and, at the same time, profoundly influences the immune and inflammatory reactions, increasing the rate of severe complications and death among diabetes patients. Therefore, understanding the underlying mechanisms behind this interplay is critical for effective treatment. Furthermore, COVID-19 also brings new factors to the equation of managing diabetes. Although the virus thoroughly relies on the ACE2 receptor for viral entry, DPP4 is a substitute receptor. However, glucose-lowering DPP4 inhibitors provide only a minor association with COVID-19 vulnerability. Also, the SGLT2 inhibitors are contraindicated in certain conditions with COVID-19, and hence, insulin is generally recommended as a first-line treatment for acute glycemic control in hospitalized or critically ill COVID-19 patients, particularly those with severe hyperglycemia or diabetic ketoacidosis. COVID-19-associated aggravating factors, such as cardiovascular disease, chronic kidney disease, and neuropathy, predispose people with diabetes to severe conditions. Thus, it is important to explore this speculation, and the present review aims to understand this complex interaction during patient care models and specify the therapeutic approaches to address this problematic convergence of two substantial health concerns.