Dipeptidyl Peptidase-4 Inhibitors Research Articles

Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications.

This review explores the pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of diabetes and its complications, highlighting the therapeutic potential of various oral hypoglycemic drugs targeting this pathway. NLRP3 inflammasome activation, triggered by metabolic stressors like hyperglycemia, hyperlipidemia, and free fatty acids (FFAs), leads to the release of pro-inflammatory cytokines interleukin-1β and interleukin-18, driving insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. These processes contribute to diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases (CVD). Here we discuss the various transcriptional, epigenetic, and gut microbiome mediated regulation of NLRP3 activation in diabetes. Different classes of oral hypoglycemic drugs modulate NLRP3 inflammasome activity through various mechanisms: sulfonylureas inhibit NLRP3 activation and reduce inflammatory cytokine levels; sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress inflammasome activity by reducing oxidative stress and modulating intracellular signaling pathways; dipeptidyl peptidase-4 inhibitors mitigate inflammasome activation, protecting against renal and vascular complications; glucagon-like peptide-1 receptor agonists attenuate NLRP3 activity, reducing inflammation and improving metabolic outcomes; alpha-glucosidase inhibitors and thiazolidinediones exhibit anti-inflammatory properties by directly inhibiting NLRP3 activation. Agents that specifically target NLRP3 and inhibit their activation have been identified recently such as MCC950, Anakinra, CY-09, and many more. Targeting the NLRP3 inflammasome, thus, presents a promising strategy for managing diabetes and its complications, with oral hypoglycemic drugs offering dual benefits of glycemic control and inflammation reduction. Further research into the specific mechanisms and long-term effects of these drugs on NLRP3 inflammasome activity is warranted.

Comparison of the Risk of Diabetic Retinopathy Between Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus in Japan: A Retrospective Analysis of Real-World Data.

Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes mellitus (T2DM), is a leading cause of blindness and has detrimental effects on patients' quality of life. We compared the risk of DR diagnosis with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM in Japan. This Japanese retrospective cohort study used the JMDC Claims Database (data collected from January 2015 to September 2022). Patients with T2DM and no record of microvascular or macrovascular diseases who were newly treated with an SGLT2i (23,061 patients) or a DPP-4i (53,986 patients) were matched 1:1 using propensity score (10,166 per matched group). Incidence rates (IRs) and cumulative IRs of DR diagnosis were calculated for each treatment group; hazard ratio (HR) and its 95% confidence interval (CI) were calculated using Cox proportional hazard models to compare the risk between the groups. The IR of DR diagnosis was 46.23 and 57.12 per 1000 person-years in the SGLT2i and DPP-4i groups, respectively, with a significantly lower risk in the SGLT2i group than in the DPP-4i group (HR 0.83, 95% CI 0.75-0.92, P = 0.0003). In this study, the risk of DR diagnosis was lower with SGLT2i compared with DPP-4i in patients with T2DM without microvascular and macrovascular diseases in Japan. Findings suggest that early SGLT2i treatment may be beneficial in preventing DR development in early-stage T2DM. Graphical abstract available for this article.

Hepatoprotective effects of vildagliptin mitigates lung biochemical and histopathological changes in experimental hepatopulmonary syndrome model in rat

Hepatopulmonary syndrome (HPS) is a liver disease-induced pulmonary complication manifested with arterial hypoxemia. Hepatic cholestasis, encountered in several clinical situations, leads to biliary cirrhosis and HPS, both of which are best reproduced by rat common bile duct ligation (CBDL). Experience from liver transplantation suggests hepatoprotective-based therapy would be most effective in HPS treatment Dipeptidyl peptidase-4 (DPP-4) enzyme is involved in different pathogenic mechanisms of liver diseases. Vildagliptin (Vild) is a DPP-4 inhibitor which possesses favorable anti-inflammatory, anti-oxidant and anti-fibrotic effects. The present work explored hepatoprotective mechanisms of Vild and their participation in its prophylactic effectiveness in HPS induced by CBDL in rats. Male Wistar rats weighing 220–280 g were allocated into 4 groups: normal control, sham, CBDL and CBDL + Vild groups. i.p. saline was administered to the first 3 groups and i.p. Vild (10 mg/kg/day) was given to the fourth group for 6 weeks starting 2 week before CBDL. CBDL produced liver fibrosis, arterial hypoxemia and decreased survivability of rats. It altered liver functions and induced oxidative stress, pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], vasodilatory molecules [endothelin-1 (ET-1), and inducible and endothelial nitric oxide synthases] and angiogenesis-associated protein [vascular endothelial growth factor-A (VEGF-A)] in liver and lung. Vild ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL rats and reversed these biochemical alterations. Prophylactic Vild administration attenuated CBDL-induced HPS in rats via direct hepatoprotective effects in the form of anti-oxidant, anti-inflammatory, anti-angiogenic and anti-fibrotic effects beside inhibition of pathological intrahepatic vasodilatation.

SITAGLIPTIN AMELIORATES ATORVASTATIN INDUCED HEPATOTOXICITY IN RATS

Atorvastatin (ATOR) is the most widely used statin for the treatment of hypercholesterolemia, which is the most common cause of severe liver injury. Sitagliptin is a selective dipeptidyl peptidase-4 inhibitor (DPP4-I) used clinically as oral anti-diabetic agent. This study aimed to identify the effect of sitagliptin (SITA) pretreatment against Atorvastatin (ATOR) induced hepatotoxicity in albino rats. Twenty-five rats were divided into five groups (5 rats in each); normal control, ATOR, SITA and two sitagliptin groups, which pretreated with sitagliptin 10 and 20 mg/kg/day in combination with ATOR 20mg /kg / day for eight consecutive days prior to ATOR. The results revealed that ATOR induced noticeable hepatic injury in the form of moderate Hepatoportal + sinusoidal congestion, all Zonal changes, moderate Cloudy swelling + hydropic degeneration, moderate Fatty change and mild Apoptosis. Biochemical analysis exposed a significant rise in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in ATOR group. Increased Proinflammatory TNF-alpha, Oxidative stress MDA and depressed antioxidant system of GSH were evident in ATOR group. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological changes induced by ATOR. In conclusion, sitagliptin ameliorated the hepatotoxicity induced by atorvastatin. This effect was probably based through suppression of inflammatory, oxidative stress and apoptotic processes. Sitagliptin might exert beneficial effect on diabetic hepatic disorders which mandate further clinical research.

Precooked Jack Bean [Canavalia ensiformis (L.) DC] Sprout: Generation of Dipeptidyl Peptidase-IV Inhibitory Peptides during Simulated Digestion.

Bioactive peptides generated from jack bean sprouts are reported to function as dipeptidyl peptidase IV (DPP-IV) inhibitors. However, no studies have investigated the effect of precooking followed by simulated digestion using pepsin-pancreatin to increase DPP-IV inhibitory peptide generation in jack bean sprouts. Therefore, the present study aimed to explore the generation of DPP-IV inhibitory peptides from precooked jack bean [Canavalia ensiformis (L.) DC] sprouts during simulated digestion with pepsin-pancreatin. The results showed that peptide fractions of the sample hydrolysate with molecular weight <1 kDa exhibited the strongest DPP-IV inhibitory activity (84.77%±0.49%) after simulated digestion. This activity was slightly greater than that (74.12%±0.85%) observed prior to simulated digestion. These findings demonstrate that the DPP-IV inhibitory activity of precooked jack bean sprouts can be retained following simulated digestion. Moreover, our investigation revealed the sequences of two novel peptides following simulated digestion with critical amino acids. The presence of alanine and glycine at the penultimate N-terminus of AAGPKP and LGDLLK confirmed the presence of DPP-IV inhibitors. Both peptide sequences are nontoxic and interact with the catalytic sites of enzymes through hydrogen bonds.

Molecular Docking and ADMET Profiling of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin from Dalbergia sissoo: In Silico Prediction in Antidiabetic Potential

Molecular Docking and ADMET Profiling of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin from Dalbergia sissoo: In Silico Prediction in Antidiabetic Potential

Novel Bioactive Peptides from Red Bigeye (Priacanthus macracanthus) Flesh Protein

Red bigeye (Priacanthus macracanthus) is a common fish species in Malaysia. This study reported an in silico assessment of the main proteins in red bigeye flesh as precursors for bioactive peptides. Six major proteins were chosen as precursors from the proteomic profiles of red bigeye proteins. Analyses using the BIOPEP-UWM database found that Protein number 4 gave the highest total number of bioactive peptides (5052 peptides), with dominant bioactivity in angiotensin-I-converting enzyme (ACE) inhibition (1571 peptides) and dipeptidyl peptidase-IV (DPP-IV) inhibition (2238 peptides). The ACE inhibitors had a frequency of bioactive fragment occurrences (A) of 0.4098, while the DPP-IV inhibitors gave a frequency of 0.5805. In silico proteolysis using BIOPEP-UWM found that pepsin (pH &gt; 2) was the most promising proteinase in releasing a high number of DPP-IV and ACE inhibitory peptides. A novel peptide with significant potential was identified as QYKF. This study shows that red bigeye is a potential source of antihypertensive and antidiabetic peptides.

Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis.

With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package "CancerSubtype" and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe2+ with commercial FerroOrange kits. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.

Perioperative Management Of Diabetes Mellitus In Older Hip Fracture Patients

Abstract Background Hip fracture is one of the most serious injuries sustained by older adults worldwide, associated with increased morbidity and almost 25% mortality at one year. Pre-existing comorbidity worsens prognosis, e.g. hip fracture patients with Diabetes Mellitus (DM) have increased mortality rates, worse functional outcomes, and higher post-operative complications rates. Perioperative blood glucose optimisation may improve outcomes, however this can be challenging due to periods of fasting and reduced intake, as well as complications such as infection. Local guidelines for the peri-operative management of DM have been developed and are sign-posted in our hip fracture integrated admission document. This audit aimed to compare current practice with those recommended in local guidance. Methods Since 1st January 2024, 31 hip fracture patients aged ≥65 years with DM have been admitted. Charts were available on twenty patients, and hence reviewed. Results Of 20 patients, four were on insulin; 13 on metformin; four on sulphonylureas; five on SGLT2 inhibitors; and six on DPP4 inhibitors. No intraoperative hypoglycemic events nor episodes of Diabetic Ketoacidosis were documented; however, ketones were not checked in the majority of patients during admission. Eleven (55%) had HbA1C either done in the previous six months or during admission. Blood Sugar Levels were checked on admission in 9/20 (45%). The protocol was followed in only one patient on insulin; and 5/13 metformin patients. The protocol was followed in all Sulphonylurea prescriptions, and in 4/5 SGLT2 inhibitor prescriptions, however these medications were not held by the Orthopaedic team, rather by nursing staff while the patient was fasting pre-operatively. Conclusion This audit demonstrates poor adherence to local guidance on peri-operative management of diabetes, particularly perioperative insulin adjustments. We aim to develop an educational intervention (including group teaching, plus distribution of flashcards and posters) for Orthopaedic SHOs and interns and re-audit in the coming months.

Glucose-lowering drugs and liver-related outcomes among individuals with type 2 diabetes: A systematic review of longitudinal population-based studies.

While randomized controlled trials data on the long-term effect of glucose-lowering drugs (GLDs) on liver-related outcomes are lacking, population-based studies have evaluated the associations of GLDs with liver-related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population-based studies evaluating the effects of GLDs on liver-related outcomes in people with T2D. PubMed, Web of Science, and Embase databases were systematically searched for population-based studies testing the associations of GLDs with liver-related outcomes in individuals with T2D and no liver disease other than non-alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP4Is). Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow-up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver-related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP-1 RAs demonstrated a significant association with reduced liver-related mortality. Observational data from population-based studies suggest that GLDs such as SGLT2is are associated with beneficial long-term liver-related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long-term follow-up, are needed to confirm these findings. PROSPERO CRD442024536872.

Sodium-glucose Cotransporter-2 Inhibitors versus Dipeptidyl Peptidase IV Inhibitors and Risk of Dementia Among Patients with Type 2 Diabetes and Comorbid Mental Disorders: A Population-based Cohort Study

AimTo evaluate whether the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors which have shown potential neuroprotective effects, is associated with lower risk of dementia in patients with type 2 diabetes (T2D) and comorbid mental disorders, who are considerably more susceptible to dementia. MethodsUsing the nationwide healthcare data of South Korea between 2010 and 2022, we conducted a retrospective cohort study among patients with T2D and comorbid mental disorders initiating SGLT2 inhibitors versus active comparator (Dipeptidyl Peptidase IV (DPP4) inhibitors). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years of incident dementia were estimated after weighting by propensity score fine stratification method. ResultsOver a 4.8-year median follow-up, SGLT2 inhibitors were associated with a 12% lower risk of dementia compared with DPP4 inhibitors (11.31 vs. 12.86 events per 1000 person years; HR 0.88, 95% CI 0.84 to 0.92; RD -1.55, -2.13 to -0.97). The results were consistent when stratified by age, sex, individual component, severe mental disorders, presence of insulin, history of cardiovascular disease, or history of hypertension. ConclusionsSGLT2 inhibitors versus DPP4 inhibitors were associated with a lower risk of incident dementia in patients with T2D and comorbid mental disorders. Further randomized controlled trials are required to confirm our findings.

Bioactive Peptides from Corn (Zea mays L.) with the Potential to Decrease the Risk of Developing Non-Communicable Chronic Diseases: In Silico Evaluation.

Studies have shown that corn (Zea mays L.) proteins, mainly α-zein, have the potential to act on therapeutic targets related to non-communicable chronic diseases, such as high blood pressure and type 2 diabetes. Enzymatic hydrolysis of proteins present in foods can result in a great diversity of peptides with different structures and possible bioactivities. A review of recent scientific research papers was performed to show evidence of the bioactive properties of corn peptides by in vitro assays. The α-zein amino acid sequences were identified in the UniProtKB protein database and then analyzed in the BIOPEP database to simulate enzymatic digestion and verify the potential biological action of the resulting peptides. The peptides found in the BIOPEP database were categorized according to the probability of presenting biological action using the PeptideRanker database. The aim was to use existing data to identify in silico the potential for obtaining biologically active peptides from α-zein, the main storage protein of corn. The analysis showed that the majority of peptide fragments were related to the inhibition of angiotensin-converting enzyme, followed by the inhibition of dipeptidyl peptidase IV and dipeptidyl peptidase III. Many drugs used to treat high blood pressure and type 2 diabetes work by inhibiting these enzymes, suggesting that corn peptides could be potential alternative agents. In vitro studies found that the primary bioactivity observed was antioxidative action. Both in vitro and in silico approaches are valuable for evaluating the bioactive properties resulting from protein hydrolysis, such as those found in α-zein. However, conducting in vitro studies based on prior in silico evaluation can be more efficient and cost-effective.

Exploring the Potential of Moringa Oleifera Phytochemicals as Inhibitors of Dipeptidyl Peptidase-4 (DPP-4) in Diabetes Mellitus: A Molecular Docking Approach

Abstract Diabetes mellitus (DM) is a global health concern characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or both. Type 2 diabetes (T2DM), the most prevalent form, is largely driven by obesity and a sedentary lifestyle, contributing to over 95% of diabetes cases worldwide. The current treatment regimens for T2DM, including Dipeptidyl Peptidase-4 (DPP-4) inhibitors, aim to enhance insulin secretion but are often associated with adverse side effects. This has intensified the search for natural, safer alternatives with comparable efficacy. Moringa oleifera, a highly valued plant with an extensive history in traditional medicine, has shown promising antidiabetic properties. This research explores the potential of Moringa oleifera-derived phytochemicals as natural DPP-4 inhibitors using in-silico molecular docking techniques. The study identifies and evaluates the binding affinities of these phytochemicals to the DPP-4 enzyme, aiming to predict their inhibitory potential and minimal side effects, thereby contributing to the development of novel, safer hypoglycemic drugs. The results indicate the compounds’ potential as effective DPP-4 inhibitors with promising hypoglycemic properties. Specifically, piceatannol exhibited the highest binding affinity of -7.9 kcal/mol, whereas vanillic acid had the lowest at -5.7 kcal/mol. This study underscores the potential of Moringa oleifera as a natural, safer alternative in the development of novel anti-diabetic drugs, contributing to the growing body of research on plant-based therapeutics for diabetes management.

Microbiota-derived PPAR-γ signaling and risk of bacterial enteric infection: insight from thiazolidinedione users in a US population-based study.

The ongoing antimicrobial resistant crisis heralds the need for new therapeutics against enteric infection. In mouse models, colon epithelial peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling limits oxygen and nitrate luminal bioavailability, thereby preventing bacterial pathogen colonization. However, whether this mechanism operates similarly in humans remains uncertain. To investigate, we used the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists. Among 85,117 thiazolidinedione users, we observed a 22-49% lower risk of bacterial enteric infections compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors. These findings support the potential protective role of PPAR-γ signaling against bacterial enteric infection and call for further clinical investigation.

Comparative Study of Hypovitaminosis B12 Associated with Metformin in Combination with Sulfonylurea or Dpp-4 Inhibitors

Comparative Study of Hypovitaminosis B12 Associated with Metformin in Combination with Sulfonylurea or Dpp-4 Inhibitors

Causal relationship between novel antidiabetic drugs and ischemic stroke: a drug-targeted Mendelian randomization study.

The escalating global economic burden of ischemic stroke poses a significant public health challenge amid global aging trends. The broad therapeutic efficacy of new antidiabetic drugs may offer new options in the prevention and treatment of ischemic stroke. Consistent conclusions regarding the relationship between novel antidiabetic agents and the risk of ischemic stroke remain elusive, and the causal relationship deserves further investigation. Three novel antidiabetic drug targets were selected, and cis-expression quantitative trait loci (cis-eQTL) were screened as instrumental variables. Genetic association data for ischemic stroke were obtained from the Genome-wide Association Study (GWAS) database. Mendelian randomization (MR) analysis, facilitated by R software, calculated MR estimates for each single nucleotide polymorphism (SNP), and meta-analysis was performed using five methods. To ensure robustness, sensitivity analyses, heterogeneity analyses, horizontal pleiotropy analyses, and co-localization analyses were conducted for significant MR associations. Three eQTLs for antidiabetic drug genes served as instrumental variables, utilizing a GWAS dataset comprising 34,217 cases and 406,111 controls for ischemic stroke. Genetic variants in glucagon-like peptide-1 receptor agonists (GLP-1 RA) targets exhibited a positive correlation with ischemic stroke risk (OR 1.06, 95% CI 1.04-1.08, P = 0.000), while genetic variation in dipeptidyl peptidase 4 inhibitors (DPP-4i) targets showed a negative association with ischemic stroke risk (OR 0.93, 95% CI 0.89-0.97, P = 0.003). Sensitivity analyses supported robust conclusions, revealing no heterogeneity or horizontal pleiotropy. This study found that GLP-1 RA and DPP-4i were associated with an increased risk of ischemic stroke by MR analysis. Although sensitivity analyses provide support for this result, it contradicts previous knowledge. Therefore, the results of this study still need to treated with caution. Updated and more in-depth GWAS data and high-quality real-world data are expected to validate the results.

The impact of vildagliptin as an add-on therapy on matrix metalloproteinase-14 levels, liver stiffness and subclinical atherosclerosis in adolescents with type 1 diabetes and non-alcoholic steatohepatitis: A randomized controlled trial.

Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis. To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT). Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT. By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated. Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression.

Cofrogliptin once every 2 weeks as add-on therapy to metformin versus daily linagliptin in patients with type 2 diabetes in China: A randomized, double-blind, non-inferiority trial.

We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase-4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China. In this phase 3 randomized, double-blind, active-controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add-on treatment to metformin, for 24 weeks. Eligible patients could enter an open-label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non-inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment. Overall, 465 patients entered the 24-week treatment period (median age: 57.0 years). The least-squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was -0.96 (0.063), -0.99 (0.064) and -1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between-group difference met the predefined margin for non-inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24-week treatment period was similar between treatment groups. There were no serious hypoglycaemic events. In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose-lowering effect of cofrogliptin (Q2W) was non-inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment.

Advances in the Insulin-Heart Axis: Current Therapies and Future Directions.

The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.

Extended duration linagliptin nanoparticles: a novel, safe and effective future of diabetes treatment?

Dear Editor, Diabetes Mellitus (DM), a chronic disease characterised by hyperglycaemia caused by either underproduction of insulin or defective insulin action, has become more prevalent globally; affecting 1 in every 10 adults over the past years with type 2 diabetes being more common in the low- and middle-income countries and type 1 in high-income countries (1). Pakistan, being a lower-middle-income country, has a 26.7% prevalence of diabetes and age-adjusted comparative prevalence of 30.8% affecting 1 in approximately every 4th adult (2). The current guidelines for the management of diabetes include insulin, metformin, sulfonylureas, and sodium-glucose co-transporters type 2 (SGLT-2) inhibitors. However, hypoglycaemia, weight gain, gastrointestinal problems and contraindication of their use in patients with pre-existing renal diseases pose problems for clinicians. Poor patient compliance in following the regular antidiabetic regimen also make treatment plans ineffective. Thus, newer drugs are constantly being researched (3). Metformin has been an excellent treatment option with only a slight risk for some specific patients to develop lactic acidosis. It is the most commonly prescribed medication for DM. Another drug, Linagliptin (Lina) was approved by the FDA in 2011 as an effective dipeptidyl peptidase inhibitor for the treatment of DM. It has been used as monotherapy and in combination with dapagliflozin, an SGLT2 inhibitor, for the treatment of diabetes in patients with a history of metformin therapy. However, its use was limited due to its low bioavailability (4). Recent research suggests that the extended duration (ED) Lina via the use of poly d, l-lactic-co-glycolic acid (PLGA) polymers in nanoparticle form could be beneficial in the management of type 2 DM. It has an increased bioavailability, fewer reported side effects and a reduced need for regular dosage. Furthermore, the use of nanoparticles facilitates a targeted delivery of the drug which may omit the pain that is caused by the use of implants (5). Lina is also thought to be effective in Type 3 Diabetes which causes Alzheimer’s disease. As dementia can lead to forgetting to take medications regularly, the ED Lina, which is taken once weekly, may be a suitable option. This new formulation is being considered for its better safety profile compared to other antidiabetics and its effectiveness in controlling HbA1C both as monotherapy and in combination therapy (4,6) ---Continue