Dipeptidyl Peptidase-4 Inhibitor Treatment Research Articles

A case of immunoglobulin G4-related kidney disease manifesting after dipeptidyl peptidase-4 inhibitor treatment.

A 68-year-old man with type 2 diabetes mellitus was admitted with decreased renal function. He had high IgG4 (1070mg/dL) and hypocomplementemia (CH50, 25U/mL). Kidney biopsy showed tubulointerstitial nephritis with IgG4-positive plasma cell infiltration. Four years later, a second kidney biopsy revealed a new manifestation of membranous nephropathy and tubulointerstitial nephritis with exacerbated fibrosis formation. Six years later, the patient developed bullous pemphigoid, which was thought to be caused by DPP4 inhibitors, so DPP4 inhibitor treatment was discontinued. The use of DPP4 inhibitors correlated with changes in renal function, and the patient was diagnosed with IgG4-related kidney disease related to DPP4 inhibitors.

Arachidonic acid alleviates autoimmune diabetes in NOD mice

BackgroundArachidonic acid (AA) is considered to link nutrient metabolism, to inflammation and immunity, suggesting it may have a role in autoimmune diseases. Our previous study suggests that DPP-4 inhibitors (DPP-4i) might regulate AA – relative signaling in type 1 diabetes. AimsTo examine the effect of AA on autoimmune diabetes and its cross-talk with DPP-4i in The Non-Obese Diabetic (NOD) mice. MethodsThe NOD mice were divided randomly and equally into three groups: AA group, AA plus DPP-4i group and control group. The incidence of diabetes, blood glucose, insulitis and cytokine profiles were monitored. At the end of the experiment, pancreatic tissues were stained by H&E. Serum cytokine profiles were examined using a Mesco Scale Discovery multiplexed-assay kit. ResultsEven though AA or AA plus DPP-4i treatment has no effect on incidence of diabetes and weight, AA treatment reduces blood glucose, preserves islet morphology and alleviates inflammatory cell infiltration into pancreatic islets in NOD mice, accompanying with increased serum levels of IL-10, IL-1 β, IL-6, IL-5, KC/GRO and TNF-α and decreased serum levels of IL-2. ConclusionWe observed that AA treatment alleviates autoimmune diabetes in NOD mice by reducing hyperglycemia, alleviating insulitis and improving cytokine profiles. DPP-4i might alleviate the effect of AA by cross-talk. We provide evidence of AA treatment to alleviate type 1 diabetes in NOD mice, which may provide a novel therapeutic option for type 1 diabetes.

Meta-Analysis on the Association Between DPP-4 Inhibitors and Bone Mineral Density and Osteoporosis

Background Type 2 Diabetes Mellitus (T2DM) frequently coexists with osteoporosis and reduced bone mineral density (BMD). Dipeptidyl peptidase-4 inhibitors (DPP-4i), a class of antihyperglycemic agents, are commonly employed in T2DM treatment. However, the influence of DPP-4i on bone health remains unclear and debated. This meta-analysis is conducted to explore the relationship between the use of DPP-4i and changes in BMD, as well as the prevalence of osteoporosis among T2DM patients.Methods We conducted a comprehensive search in PubMed, Embase, and Cochrane Library and Web of Science databases for relevant studies published up until June 2023. Studies included in the meta-analysis were those investigating T2DM patients under DPP-4i treatment, and examining the effects on BMD and osteoporosis. Random-effects models and fixed-effect models were utilized to compute the pooled effects. Heterogeneity among the included studies was evaluated using I² statistics.Results This meta-analysis incorporated a total of 10 studies, encompassing a combined population of 214,541 individuals. The results from this meta-analysis indicated an increase in BMD following DPP-4i usage (SMD 0.15, 95 % confidence interval 0.03-0.26). Additionally, the risk of osteoporosis was significantly reduced (OR 0.90, 95 % confidence interval 0.86-0.94) with very low heterogeneity, recorded at 0 % and 53.0 % respectively. No publication bias was detected in the funnel plot, and sensitivity analyses affirmed the stability of the study's conclusions.Conclusion Our results offer valuable insights into the positive impact of DPP-4i on bone health in T2DM patients, contributing to informed clinical decision-making. These findings may inform the development of more comprehensive T2DM management strategies that account for bone health.

The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.

DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF-β/Smad Signaling Pathway.

This study investigated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4is) on fibrosis after glaucoma filtering surgery with clinical data and an in vitro model that used transforming growth factor-β (TGF-β) to induce human Tenon's fibroblast (HTF) fibrosis. The medical records of 41 eyes of 35 patients with diabetes with neovascular glaucoma (NVG) who received initial trabeculectomy were retrospectively reviewed. The surgical success rate was compared between cases that received (n = 23) and did not receive (n = 18) DPP-4i treatment for diabetes. The antifibrotic effects of linagliptin (a DPP-4i) were evaluated with quantitative real-time PCR for fibrosis markers (α-smooth muscle actin, collagen Iα, and fibronectin), a scratch assay, and a collagen gel contraction assay of primary cultured HTFs treated with TGF-β1 and linagliptin. Western blotting analysis was performed to evaluate the levels of phosphorylated Smad2 and Smad3 in the presence of linagliptin. The Kaplan-Meier curve for bleb survival was higher in patients who received DPP-4is (P = 0.017, log-rank test). The in vitro experiments demonstrated that treatment with linagliptin attenuated the elevated levels of fibrosis markers induced by TGF-β1 in HTFs. Linagliptin treatment also prevented the migration and gel contraction of HTFs. Linagliptin inhibited the phosphorylation of Smad2 and Smad3, which is the canonical pathway of TGF-β signaling. The current study indicates the potential effect of DPP-4is for maintaining bleb function after glaucoma filtering surgery in patients with diabetes with NVG. Our results demonstrate that linagliptin attenuates fibrotic change in HTFs by inhibiting TGF-β/Smad signaling.

Re-evaluation of dipeptidyl peptidase-4 inhibitors in patients with heart failure and diabetes mellitus

ObjectivesThe question of whether dipeptidyl peptidase-4 inhibitors (DPP-4i) should be preferred as new glucose-lowering agents in heart failure is controversial. This studyaimed to evaluate the effects of DPP-4i treatment on all-cause mortality and cardiovascular outcomes in patients with heart failure. MethodsWe searched for available studies of DPP-4i therapy in heart failure and performed a pooled analysis. Outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), acute coronary syndrome, and acute myocardial infarction. ResultsTreatment with DPP-4i did not reduce the risk of all-cause death, cardiovascular death, or hospitalization for heart failure. Subgroup analyses showed that DPP-4i significantly reduced all-cause mortality in trials with > 40% female patients (OR 0.30, 95% CI [0.16, 0.58], P = 0.0003) and in trials with > 20% patients with heart failure with preserved ejection fraction (HFpEF) (OR 0.34, 95% CI [0.19, 0.60], P = 0.0003). Changes in LVEF and LVEDV showed no statistical differences between the 2 groups. Accordingly, DPP-4i did not alter the risk of acute coronary syndrome and acute myocardial infarction. ConclusionsDPP-4i may reduce all-cause mortality in heart failure patients in subgroups of women and HFpEF and has a high coronary safety profile.

Comparative Efficacy of Novel Antidiabetic Drugs on Albuminuria Outcomes in Type 2 Diabetes: A Systematic Review.

Albuminuria, or elevated urinary albumin-to-creatine ratio (UACR), is a biomarker for chronic kidney disease that is routinely monitored in patients with type 2 diabetes (T2D). Head-to-head comparisons of novel antidiabetic drugs on albuminuria outcomes remain limited. This systematic review qualitatively compared the efficacy of novel antidiabetic drugs on improving albuminuria outcomes in patients with T2D. We searched the MEDLINE database until December 2022 for Phase 3 or 4 randomized, placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on changes in UACR and albuminuria categories in patients with T2D. Among 211 records identified, 27 were included, which reported on 16 trials. SGLT2 inhibitors and GLP-1 RAs decreased UACR by 19-22% and 17-33%, respectively, versus placebo (P < 0.05 for all studies) over median follow-up of ≥ 2years; DPP-4 inhibitors showed varying effects on UACR. Compared with placebo, SGLT2 inhibitors decreased the risk for albuminuria onset by 16-20% and for albuminuria progression by 27-48% (P < 0.05 for all studies) and promoted albuminuria regression (P < 0.05 for all studies) over median follow-up of ≥ 2years. Evidence on changes in albuminuria categories with GLP-1 RA or DPP-4 inhibitor treatment were limited with varying outcome definitions across studies and potential drug-specific effects within each class. The effect of novel antidiabetic drugs on UACR or albuminuria outcomes at ≤ 1year remains poorly studied. Among the novel antidiabetic drugs, SGLT2 inhibitors consistently improved UACR and albuminuria outcomes in patients with T2D, with continuous treatment showing long-term benefit.

Association of Dipeptidyl Peptidase-4 Inhibitors Use with Reduced Risk of Hepatocellular Carcinoma in Type 2 Diabetes Patients with Chronic HBV Infection

Previous studies have indicated that HBV infection and T2DM are the factors that increase the risk of developing HCC. The experimental evidence has shown that antiglycemic agents may reduce the risk of HCC. However, the effect of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) on the risk of HCC in T2DM patients with chronic HBV infection remains unclear. In this retrospective cohort study, we extracted patients with T2DM and chronic HBV infection from the National Health Insurance Research Database (NHIRD) in Taiwan. The cases were divided into DPP-4 inhibitors use and non-use groups, according to whether they received DPP-4 inhibitors treatment, and the risk of HCC was compared between the two groups. At the end of the follow-up, approximately 2.33% of DPP-4 inhibitors users had received an HCC diagnosis compared with 3.33% of non-DPP-4 inhibitors users (p < 0.0001). After multivariate adjustment, DPP-4 inhibitors users showed a significant reduction in HCC risk (adjusted hazard ratios (aHRs): 0.53; 95% confidence intervals (CIs): 0.44-0.65). In conclusion, this population-based retrospective cohort study indicated that, in T2DM patients with chronic HBV infection, the use of DPP-4 inhibitors significantly reduced the risk of developing HCC compared with non-DPP-4 inhibitors use.

Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients With Type 2 Diabetes and Varying Baseline HbA1c Levels

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy has been associated with cardiovascular benefits and a few adverse events; however, whether the comparative effectiveness and safety profiles vary with differences in baseline hemoglobin A1c (HbA1c) levels is unknown. To compare cardiovascular effectiveness and safety of treatment with SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP-4i) in adults with type 2 diabetes (T2D) (1) overall and (2) at varying baseline HbA1c levels. A new-user comparative effectiveness and safety research study was conducted among 144 614 commercially insured adults, initiating treatment with SGLT2i or DPP-4i and with a recorded T2D diagnosis at baseline and at least 1 HbA1c laboratory result recorded within 3 months before treatment initiation. The intervention consisted of the initiation of treatment with SGLT2i or DPP-4i. Primary outcomes were a composite of myocardial infarction, stroke, or all-cause death (modified major adverse cardiovascular events [MACE]) and hospitalization for heart failure (HHF). Safety outcomes were hypovolemia, fractures, falls, genital infections, diabetic ketoacidosis (DKA), acute kidney injury (AKI), and lower-limb amputation. Incidence rate (IR) per 1000 person-years, hazard ratios (HR) and rate differences (RD) with their 95% CIs were estimated controlling for 128 covariates. A total of 144 614 eligible adults (mean [SD] age, 62 [12.4] years; 54% male participants) with T2D initiating treatment with a SGLT2i (n = 60 523) or a DPP-4i (n = 84 091) were identified; 44 099 had an HbA1c baseline value of less than 7.5%, 52 986 between 7.5% and 9%, and 47 529 greater than 9%. Overall, 87 274 eligible patients were 1:1 propensity score-matched: 24 052 with HbA1c less than 7.5%; 32 290 with HbA1c between 7.5% and 9%; and 30 932 with HbA1c greater than 9% (to convert percentage of total hemoglobin to proportion of total hemoglobin, multiply by 0.01). The initiation of SGLT2i vs DPP-4i was associated with a reduction in the risk of modified MACE (IR per 1000 person-years 17.13 vs 20.18, respectively; HR, 0.85; 95% CI, 0.75-0.95; RD, -3.02; 95% CI, -5.23 to -0.80) and HHF (IR per 1000 person-years 3.68 vs 8.08, respectively; HR, 0.46; 95% CI, 0.35 to 0.57; RD -4.37; 95% CI, -5.62 to -3.12) over a mean follow-up of 8 months, with no evidence of treatment effect heterogeneity across the HbA1c levels. Treatment with SGLT2i showed an increased risk of genital infections and DKA and a reduced AKI risk compared with DPP-4i. Findings were consistent by HbA1c levels, except for a more pronounced risk of genital infections associated with SGLT2i for HbA1c levels of 7.5% to 9% (IR per 1000 person-years 68.5 vs 22.8, respectively; HR, 3.10; 95% CI, 2.68-3.58; RD, 46.22; 95% CI, 40.54-51.90). In this comparative effectiveness and safety research study among adults with T2D, SGLT2i vs DPP-4i treatment initiators had a reduced risk of modified MACE and HHF, an increased risk of genital infections and DKA, and a lower risk of AKI, regardless of baseline HbA1c.

Anagliptin twice-daily regimen improves glycaemic variability in subjects with type 2 diabetes: A double-blind, randomized controlled trial.

To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P=.215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P=.014) in the sitagliptin group, with a statistically significant difference (P=.009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Effects of second-line antihyperglycemic drugs on the risk of chronic kidney disease: applying a target trial approach to a hospital-based cohort of Thai patients with type 2 diabetes

BackgroundThe reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD).MethodsA real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment.ResultsCKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively.ConclusionsOur study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.

Association of dipeptidyl peptidase-4 inhibitor use and risk of pancreatic cancer in individuals with diabetes in Japan.

This study was designed and carried out to investigate the association of dipeptidyl peptidase-4 inhibitor (DPP-4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. The JMDC Claims Database, which contains the medical and prescription information of Japanese employment-based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP-4is or other oral glucose-lowering agents (GLAs). Individuals with diabetes who received DPP-4is (n= 61,430) or other oral GLAs (n= 83,304) were analyzed. Follow-up periods (median [interquartile range]) were 17 months (8-33) for DPP-4is and 14 months (7-28) for other oral GLAs. Kaplan-Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log-rank test: all, P= 0.7140; hospitalized, P= 0.3446). Cox proportional hazards models showed that use of DPP-4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8-1.3, P= 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8-1.4, P= 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. This database study shows that there is not a significant PC risk due to DPP-4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes.

There are relatively few data on noncardiovascular (non-CV) long-term clinical outcomes of dipeptidyl peptidase 4 inhibitor (DPP4i) treatment. We aimed to evaluate some non-CV effects of DPP4is in patients with diabetes. Based on data from the National Health Insurance Service database in Korea (2007-2018), we conducted 3 pairwise comparisons of metformin-combined antidiabetic therapies in adult patients with diabetes: DPP4is vs (1) all other oral antidiabetic agents, (2) sulfonylureas/glinides, and (3) thiazolidinediones (TZDs). Major outcomes were liver cirrhosis, end-stage renal disease (ESRD), and cancers in the liver, kidney, and pancreas. Adjusted hazard ratios (HRs) and 95% CIs for the outcomes were estimated using an adjusted Cox model. Of the 747 124 patients included, 628 217 had received DPP4i therapy for a mean duration of 33.8 ± 25.0 months. Compared with TZD therapy, DPP4i therapy was associated with higher adjusted HRs [95% CIs] for liver cirrhosis (1.267 [1.108-1.449]), ESRD (1.596 [1.139-2.236]), liver cancer (1.117 [1.011-1.235]), and pancreatic cancer (1.158 [1.040-1.290]). Furthermore, apart from liver cirrhosis, a higher risk of each of these outcomes was associated with DPP4i use than with non-DPP4i use. The higher adjusted HRs associated with DPP4i use further increased when patients with long-term exposure to DPP4is were analyzed. DPP4i therapy in patients with diabetes was associated with a higher risk of liver cirrhosis and cancer, ESRD, and pancreatic cancer than TZD therapy and, except for liver cirrhosis, the risk of these outcomes was greater with DPP4i treatment than with non-DPP4i treatment.

Dipeptidylpeptidase (DPP)-4 inhibitor therapy increases circulating levels of anti-inflammatory soluble frizzle receptor protein (sFRP)-5 which is decreased in severe COVID-19 disease

Obesity and type 2 diabetes (T2D) show an increased risk for a severe COVID-19 disease. Treatment with DPP4 inhibitor (DPP4i) results in reduced mortality and better clinical outcome. Here, we aimed to identify potential mechanisms for the observed DPP4i effect in COVID-19. Comparing T2D subjects with and without DPP4i treatment, we identified a significant increase of the anti-inflammatory adipokine sFRP5 in relation to DPP4 inhibition. sFRP5 is a specific antagonist to Wnt5a, a glycopeptide secreted by adipose tissue macrophages acting pro-inflammatory in various diseases. We therefore examined sFRP5 levels in patients hospitalised for severe COVID-19 and found significant lower levels compared to healthy controls. Since sFRP5 might consequently be a molecular link for the beneficial effects of DPP4i in COVID-19, we further aimed to identify the exact source of sFRP5 in adipose tissue on cellular level. We therefore isolated pre-adipocytes, mature adipocytes and macrophages from adipose tissue biopsies and performed western-blotting. Results showed a sFRP5 expression specifically in mature adipocytes of subcutaneous and omental adipose tissue. In summary, our data suggest that DPP4i increase serum levels of anti-inflammatory sFRP5 which might be beneficial in COVID-19, reflecting a state of sFRP5 deficiency.

Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials

ObjectiveTo examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases.DesignSystematic review and pairwise and network meta-analysis.Data sourcesPubMed, EMBASE, Web of Science, and CENTRAL from inception until 31...

DPP4 Inhibitors Turnover is Important in Controlling Blood Glucose in Type 2 Diabetes

We should put into consideration that some humans are genetically more susceptible to develop type 2 diabetes than others. Of them, transcription factor 7-like 2 (TCF7L2) is the gene which is more accusative. Dipeptidyl peptidase 4 Inhibitors (DPP-4 inhibitors) are considered as a comparatively new class of anti hyperglycemic drugs, the first agent of this group was approved by FDA in 2006. This group known as gliptins work in a physiological manner, as we all know ,enteroendocrine l cells in the intestine produce glucagon-like peptide-1,a hormone acting on glp1 receptors on pancreatic beta cells, leading to physiological insulin release. Dpp 4 inhibitors are classified into 3 classes according to subsite interaction in the dpp4 enzyme. Materials and methods: 200 patients of type2 diabetes mellitus followed in a private clinic for 6 months in observational prospective study. Results: The results of our study show that turnover of dpp4 inhibitors in treatment of type 2 diabetes decrease hba1c and improve treatment outcomes. Conclusion: Dpp4 inhibitors turnover in diabetes mellitus treatment give a good control of type 2 diabetes better than using on drug for a long time.

ZD-2, a novel DPP4 inhibitor, protects islet β-cell and improves glycemic control in high-fat-diet-induced obese mice

AimsDipeptidyl peptidase-4 (DPP-4) inhibitors have been extensively used for the treatment of type 2 diabetes mellitus. Nevertheless, side effects like sore throat and diarrhea also occur in DPP-4 inhibitors treatment. The study aims to identify and develop novel DPP-4 inhibitors with better therapeutic profiles. Materials and methodsHere we synthesized a series of vildagliptin analogs, and among which, ZD-2 showed the moderate inhibition of DPP-4 activity compared with vildagliptin. High-fat-diet (HFD) mice were treated with ZD-2 (4.5 and 7.5 mg/kg) or vildagliptin (6 mg/kg) for 7 weeks following the examinations of metabolic index and pancreatic β-cell function. Mouse pancreatic cell line MIN6 was used to evaluate β-cell function, and intestinal enteroendocrine cell line STC-1 was used to evaluate the expression of gut hormones. Key findingsThe IC50 of ZD-2 was over 30-fold higher than vildagliptin. However, both ZD-2 and vildagliptin treatment showed comparable effects on improving glucose tolerance and reducing the steatosis of liver and fat mass in HFD mice. Moreover, ZD-2 exerted β-cell-protective actions by preserving islet β-cell mass and increasing the expression of functional β-cell-related genes. Additionally, ZD-2 also stimulated the expression of gut hormones in STC-1 cells. SignificanceZD-2 showed comparable anti-diabetic activities in HFD-fed mice although its lower potency on inhibition of DPP-4 compared with vildagliptin. Protection of β-cell function might contribute to its anti-diabetic effects.

Bullous Pemphigoid Associated with Dipeptidyl Peptidase 4 Inhibitors for the Treatment of Type 2 Diabetes: A Multicenter Study in Istanbul.

ObjectivesRecent studies have revealed an association between dipeptidyl peptidase 4 inhibitors (DPP4i) and development of bullous pemphigoid (BP). The main aim of our study is to evaluate the association between DPP4i treatment and BP development. The secondary endpoints were to evaluate clinical characteristics and biochemical parameters of the DPP4i associated BP cases and determine the differences of DPP4i associated BP disease than non-DPP4i associated BP cases.MethodsWe designed a retrospective case-control study, comparing type 2 diabetic 58 BP cases to 75 type 2 diabetic controls. Data were collected from three dermatological departments in Istanbul/Turkey, from November 1, 2008, to January 1, 2019. Medical records of each patient’s demographic, clinical characteristics, drugs used, and laboratory data were reviewed.ResultsThere was no statistical difference in age and gender between the patient and control group. The most common prescribed oral antidiabetic for both groups was metformin. The most commonly prescribed DPP4i was vildagliptin. Fourteen (24.1%) out of 58 diabetic patients with BP were using vildagliptin, 12 (20.7%) out of 58 diabetic BP patients were using linagliptin, 6 (10.3%) out of 58 diabetic BP patients were using sitagliptin, and 1 (1.7%) out of 58 diabetic BP patients were using saxagliptin. There was no significant difference between the two groups regarding the DPP4 is use (using DPPi at the time of diagnosis and not). Both groups had similar clinical characteristics, localizations, disease severity, comorbidities, treatment responses, and biochemical parameters. BP patients using DPP4i had statistically less mucosal involvement than BP patients not using DPP4i (p=0.044).ConclusionEven though there was no difference between two groups, when BP develops in diabetic patients, DPP4 is should be questioned and with cooperation with clinician’s consideration of change may be planned.

Association of dipeptidyl peptidase-4 inhibitor use and the risk of asthma development among type 2 diabetes patients.

Numerous studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4i) may regulate immunological pathways implicated in asthma. The association between DPP-4i use and risk of asthma development is limited, however. We aimed to evaluate if DPP-4i treatment in individuals with type 2 diabetes mellitus (T2DM) is associated with a lower risk and severity of asthma. We performed a population-based retrospective cohort study using the Longitudinal National Health Insurance Research database between 2008 and 2015. After one-to-four propensity score matching from 1,914,201 patients with defined criteria, we enrolled 3001 patients who were on DPP-4i (DPP-4i group) for a diagnosis of T2DM but without a diagnosis of asthma for further analysis. Cox proportional hazards regression analysis was performed to estimate and compare the risk of developing and severity of asthma, including no acute exacerbations event (No-AE), acute exacerbations (AEs), status asthmaticus (Status), and required endotracheal intubation (ET-tube intubated), between the two groups. The participants had a mean age of 66.05 ± 17.23 years and the mean follow-up time was 4.96 ± 4.39 years. The risk of asthma development was significantly lower in the DPP-4i group than in the non-DPP-4i group [adjusted hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.29-0.83; p < 0.001], with a class effect. This trend was observed for severity of asthma as No-AE (HR = 0.55; 95% CI = 0.24-0.70; p < 0.001), AE (HR = 0.57; 95% CI = 0.26-0.73; p < 0.001), and Status (HR = 0.78; 95% CI = 0.35-0.99; p = 0.047), but not in ET-tube intubated cases (HR = 0.96; 95% CI = 0.43-1.22; p = 0.258). The use of DPP-4i decreased the risk and severity of asthma with a class effect among No-AE, AE, status of asthma events, but not in ET-tube intubated events. Our report suggests that DPP-4i may play a role in attenuating the impact of asthma on incidence in the future and on more severe forms of disease exacerbation in T2DM patients.

Does DPP-4 inhibitor treatment affect the clinical outcomes of COVID-19 in type 2 diabetes mellitus patients?

OBJECTIVEWe aim to investigate whether the use of dipeptidyl peptidase inhibitors (DPP-4i) affects the severity of disease, hospital mortality, and 3-month post-discharge mortality in type 2 diabetes mellitus (T2DM) individuals with coronavirus disease 2019 (COVID-19) infection.METHODSThe study included 217 patients with type 2 diabetes hospitalized due to COVID-19 between March and October 2020. The patients included in the study were divided into two groups those using DPP-4i and those not using DPP-4i. Demographic characteristics, laboratory parameters, accompanying risk factors, concomitant comorbidities, hospital mortality, clinical course, and 3-month post-discharge mortality were compared between the patients who used DPP-4i and those who did not use.RESULTSThe duration of hospitalization was 10.96±9.16 days in the group using DPP-4i, 12.22±9.1 days in the group not using DPP-4i, and when both groups were evaluated together, it was determined as 11.91±9.11 days. The hospitalization periods were similar between DPP-4i users and non-DPP-4i users (p=0.384). The need for mechanical ventilation (p=0.478 OR 0.710 95% confidence interval [CI], 0.274–1.836) and high-flow nasal cannula (p=0.457, OR: 0.331, 95% CI: 0.41–2.67) were similar between DPP-4i users and non-users. It was determined that the mortality (p=0.208, OR: 0.409, 95% CI: 0.117–1.429) and 3-month post-discharge mortality (p=0.383) were similar in the group using DPP-4i and those not using DPP-4i.CONCLUSIONThis study demonstrated that the use of DPP-4i by patients with T2DM in catching COVID-19 does not affect the mortality due to COVID-19, the severity of COVID-19 disease, and 3-month post-discharge mortality.