Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the IC50 values were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent IC50 values 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with IC50 value of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with IC50 value of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions.

UNASSIGNED: We examined the real-world comparative safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. other newer anti-glycemic medications (dipeptidyl peptidase-4 inhibitors [DPP4i], glucagon-like peptide-1 receptor agonists [GLP1a]) in patients with and without chronic kidney disease (CKD).
UNASSIGNED: Among US Veterans with diabetes receiving care from the Veterans Affairs (VA) healthcare system over 2004-19, we identified incident users of SGLT2i vs. DPP4i vs. GLP1a monotherapy. In analyses stratified by CKD status, defined by estimated glomerular filtration rate and albuminuria, we examined associations of SGLT2i vs. DPP4i vs. GLP1a use with risk of infection-related (primary outcome) and genitourinary infection hospitalizations (secondary outcome) using multivariable Cox models.
UNASSIGNED: Among 92,269 patients who met eligibility criteria, 52% did not have CKD, whereas 48% had CKD. In the overall and non-CKD cohorts, compared to DPP4i use, SGLT2i use was associated with lower infection-related hospitalization risk (HRs [95% CIs] 0.74 [0.67-0.81] and 0.77 [0.67, 0.88], respectively), whereas GLP1a use demonstrated comparable risk. However, in the CKD cohort SGLT2i and GLP1a use were each associated with lower risk (HRs [95% CIs] 0.70 [0.61, 0.81] and 0.91 [0.84, 0.99], respectively). Propensity score-matched analyses showed similar findings in the non-CKD and CKD cohorts. In the overall, non-CKD, and CKD cohorts, SGLT2i use was associated with lower genitourinary infection hospitalization risk whereas GLP1a use showed comparable risk vs. DPP4i use.
UNASSIGNED: In a national cohort of Veterans with diabetes, compared with DPP4i use, SGLT2i use was associated with lower infection-related and genitourinary infection hospitalization risk.
UNASSIGNED: VA Health Services Research and Development, USA.

India has a high prevalence of type 2 diabetes mellitus (T2DM) with unique clinical characteristics compared to other populations. Despite advancements in diabetes therapy, a significant number of patients in India still experience poor glycemic control and complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors continue to be an important component of T2DM treatment due to their favorable efficacy and tolerability profile. Given the current scenario, there is a need to revisit the role of DPP-4 inhibitors in T2DM management in Indian patients. This consensus paper aims to provide guidance on the utilization of DPP-4 inhibitors in T2DM management from an Indian perspective. A consensus group of 100 experts developed recommendations based on an extensive literature review and discussions. The expert group emphasized the importance of timely glycemic control, combination therapy, and targeting the underlying pathophysiology of T2DM. The combinations of DPP-4 inhibitors with metformin and/or sodium-glucose transport protein-2 inhibitors are rationalized in this paper, considering their complementary mechanisms of action. This paper provides valuable insights for clinicians in optimizing the management of T2DM in the Indian population with the use of DPP-4 inhibitors and proposes an algorithm for selecting DPP-4 inhibitor-based therapies.

OBJECTIVE: To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups.
METHODS: PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years).
RESULTS: For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups.
CONCLUSIONS: The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals.

OBJECTIVE: Previous studies have shown that newer glucose-lowering drugs (GLDs), such as sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 (DPP-4) inhibitors, may decrease the risk of gout, however, the evidence remains inconclusive. This study aimed to assess the association between newer GLDs and risk of gout.
METHODS: We systematically searched electronic databases up to August 2023 to include randomized, placebo-controlled outcome trials that reported gout-related outcomes in participants with and without type 2 diabetes. A random effects network meta-analysis was conducted to estimate the risk ratio (RR) with 95% confidence interval (CI) to compare the effects of SGLT2 inhibitors, GLP-1RAs, and DPP-4 inhibitors on risk of gout.
RESULTS: This study included 22 trials involving 173,498 patients. Compared with placebo, SGLT2 inhibitors were significantly associated with decreased risk of gout (RR, 0.51; 95% CI, 0.29-0.91) while both GLP-1RAs and DPP-4 inhibitors have no significant effects on gout risk. There were no significant differences between SGLT2 inhibitors and GLP-1RAs (RR, 0.75; 95%CI, 0.31-1.82) and between GLP-1RAs and DPP-4 inhibitors (RR, 0.39; 95%CI, 0.14-1.10).
CONCLUSIONS: SGLT2 inhibitors may potentially prevent the risk of gout, however, both GLP-1RAs and DPP-4 inhibitors have neutral effects.

The DPP-4 enzyme degrades incretin hormones GLP-1 and GIP. DPP-4 inhibitors are found effective in the prevention of the degradation of incretins. Xanthine scaffold-bearing molecules are reported as potential DPP-4 inhibitors for treating type 2 diabetes mellitus, e.g. the marketed drug linagliptin. In this work, structure-guided alignment-dependent atom- and Gaussian field-based 3D-QSAR have been performed on a dataset of 75 molecules. The robustness and predictive ability of the developed multifacet 3D-QSAR models were validated on different statistical parameters and found to be statistically fit. The favorable and unfavorable pharmacophoric features were mapped for each multifacet 3D-QSAR model based on three alignment sets (1-3). A five-point common pharmacophore hypothesis was generated separately for each set of alignments. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (Compounds 12, 40 and 57) compared to reference standard linagliptin to study the binding energy and stability of target-ligand complexes. The MM-PBSA calculations revealed that the binding free energy and stability of compounds 12 (-40.324 ± 17.876 kJ/mol), 40 (-80.543 ± 21.782 kJ/mol) and 57 (-50.202 ± 16.055 kJ/mol) were better than the reference drug linagliptin (-20.390 ± 63.200 kJ/mol). The generated contour maps from structure-guided alignment-dependent multifacet 3D-QSAR models offer information about the structure-activity relationship (SAR) and ligand-target binding energy and stability data from MD simulation may be utilized to design and develop target selective xanthine-based novel DPP-4 inhibitors.Communicated by Ramaswamy H. Sarma.

OBJECTIVE: Diabetes Mellitus (DM) is a global health concern that affects millions of people globally. The present review aims to narrate the clinical guidelines and therapeutic interventions for Type 2 Diabetes Mellitus (T2DM) patients. Furthermore, the present work summarizes the ongoing phase 1/2/3 and clinical trials against T2DM.
METHODS: A meticulous and comprehensive literature review was performed using various databases, such as PubMed, MEDLINE, Clinical trials database (https://clinicaltrials.gov/), and Google Scholar, to include various clinical trials and therapeutic interventions against T2DM.
RESULTS: Based on our findings, we concluded that most T2DM-associated clinical trials are interventional. Anti-diabetic therapeutics, including insulin, metformin, Dipeptidyl Peptidase-4 (DPP-4) inhibitors, Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), and Sodium- Glucose cotransporter-2 (SGLT-2) inhibitors are frontline therapeutics being clinically investigated. Currently, the therapeutics in phase IV clinical trials are mostly SGLT-2 inhibitors, implicating their critical contribution to the clinical management of T2DM.
CONCLUSIONS: Despite the success of T2DM treatments, a surge in innovative treatment options to reduce diabetic consequences and improve glycemic control is currently ongoing. More emphasis needs to be on exploring novel targeted drug candidates that can offer more sustained glycemic control.

In this research, a sitagliptin-lignin biopolymer (SL) containing zinc selenide quantum dots (ZnSe QDs) and doxorubicin (doxo) was synthesized. The fabricated polymeric drug delivery system was characterized via FTIR, XRD, SEM, TGA, IR, and DSC. SLQD-Doxo exhibited an irregular surface with a 32 nm diameter and well-defined surface chemistry. Drug loading efficiency was assessed at different concentrations, pH levels, time intervals, and temperatures, and drug kinetics were calculated. Maximum drug release was observed at 6 μmol concentration after 24 h, pH of 6.5 and 45 °C. The maximum drug encapsulation efficiency was 81.75 %. SLQD-Doxo demonstrated 24.4 ± 1.04 % anti-inflammatory activity, and the maximum lipoxygenase inhibition in a concentration-dependent manner was 71.45 ± 2.02 %, compared to indomethacin, a standard anticancer drug. The designed system was applied to breast cancer MCF-7 cells to evaluate anticancer activity. Cytotoxicity of SLQD-Doxo resulted in 24.48 ± 1.64 dead cells and 74.39 ± 4.12 viable cells. Lignin\'s polyphenolic nature resulted in good antioxidant activity of LLQD-Doxo. The combination of SLQD-Doxo was appropriate for drug delivery at high temperatures and acidic pH of tumor cells compared to healthy cells.

BACKGROUND: DPP-4 inhibitors, or gliptins, are new oral antidiabetic drugs for type 2 diabetes. They help to regulate insulin and glucagon. These drugs have the advantage of a lower risk of hypoglycemia compared to some other diabetes medications and are typically prescribed when metformin and sulphonylureas have become less effective.
OBJECTIVE: This review analyses a range of analytical and bioanalytical methods for DPP-4 inhibitors, that use spectroscopic techniques, chromatographic, and hyphenated techniques for analysis. So far, no review comprising all DPP-4 inhibitors has been presented. The primary objective of this review is to present the analysts with various analytical and bioanalytical methods for the quantification and estimation of DPP-4 inhibitors in different matrices.
METHODS: To improve understanding, a review was carried out by creating a database of pre-existing research from digital sources such as ScienceDirect, and PubMed. The methodology is shown in the flowchart of the literature selection process.
CONCLUSIONS: The comprehensive assessment of methods for analysing DPP-4 inhibitors can be a valuable resource for researchers and healthcare practitioners. Hitherto, no review encompassing all DPP-4 inhibitors has been presented. Therefore, gaps in the data available on a particular subject, need to be required to collect data on a particular construct. The review suggests that chromatographic techniques were majorly used for analysis wherein solvents like acetonitrile, methanol, and buffer solutions were used as mobile phases that can deteriorate HPLC columns and equipment. So, scientists could investigate new methods for the assessment of DPP-4 inhibitors using more eco-friendly solvents.

Drug-induced bullous pemphigoid (DBP) may present identical to an idiopathic type of illness. Thus, DBP should be considered as a differential diagnosis when evaluating the cause of bullous pemphigoid (BP) in elderly individuals with diabetes. We present the case of a 65-year-old \"young-elderly\" female who developed bullous lesions after initiation of medication. This case report casts light on a commonly prescribed antidiabetic drug, a dipeptidyl peptidase-4 inhibitor, vildagliptin, and its unforeseen complication in the elderly. The long-term complication is BP. With long-term use, there is an increased likelihood of encountering such cases among the elderly. Thus, we recommend that DBP be considered an important early differential diagnosis among elderly diabetics presenting with initial signs and symptoms of BP.