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Dipeptidyl peptidase-4 inhibition: insights from the bench and recent clinical studies.

ABSTRACT: Atherosclerosis is the leading cause of death globally. The pathophysiology of atherosclerosis is not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. Recent advances in the understanding of DPP4 function in atherosclerosis will be discussed in this review.Multiple preclinical and clinical studies suggest DPP4/glucagon-like peptide-1 axis is involved in the development of atherosclerotic disease. However, several recent trials assessing the cardiovascular effects of DPP4 inhibition indicate enzymatic inhibition of DPP4 lacks beneficial effects on cardiovascular disease.Catalytic inhibition of DPP4 with DPP4 inhibitors alters pathways that could favor cardioprotection. Glucagon-like peptide-1 receptor-independent aspects of DPP4 function may contribute to the overall neutral effects on cardiovascular outcome seen in the outcome trials.

SUBMITTER: Zhong J

PROVIDER: S-EPMC5147592 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Dipeptidyl peptidase-4 inhibition: insights from the bench and recent clinical studies.

Zhong Jixin J Kankanala Saumya S Rajagopalan Sanjay S

Current opinion in lipidology 20161001 5

<h4>Purpose of review</h4>Atherosclerosis is the leading cause of death globally. The pathophysiology of atherosclerosis is not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. Recent advances in the understanding of DPP4 function in atherosclerosis will be discussed in this review.<h4>Recent findings</h4>Multiple preclinical and clinical studies suggest DPP4/glucago ...[more]

PMID: 27472408

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Recent Advances in Dipeptidyl-Peptidase-4 Inhibition Therapy: Lessons from the Bench and Clinical Trials.

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| S-EPMC4446505 | biostudies-literature

New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin.

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| S-EPMC6864445 | biostudies-literature

Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation.

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Dipeptidyl peptidase-IV is associated with decreased glioma growth

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2011-12-31 | E-MTAB-583 | biostudies-arrayexpress

Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors.

Project description:BackgroundIt is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.MethodsThis study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 <65.26%, T2=65.26%-76.35%, and T3 ≥76.35% by DPP-4 inhibition. We analyzed the change from baseline in glycosylated hemoglobin (HbA1c) according to DPP-4 inhibition with multiple linear regression adjusting for age, ethnicity, body mass index, baseline HbA1c, and DPP-4 activity at baseline.ResultsThe mean age was greater in the high tertile group compared with the low tertile group (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3±9.5, P<0.001) of DPP-4 inhibition. Although HbA1c at baseline was not different among tertiles of DPP-4 inhibition (P=0.398), HbA1c after 24-week treatment was lower in the higher tertile compares to the lower tertile (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). In multiple regression analysis, DPP-4 enzyme inhibition rate was not a significant determent for HbA1c reduction due to age. In subgroup analysis by tertile of DPP-4 inhibition, age was the only significant predictor and only in the highest tertile (R2=0.281, B=-0.014, P=0.024).ConclusionThis study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.

| S-EPMC8831807 | biostudies-literature

Natural phenolic compounds potentiate hypoglycemia via inhibition of Dipeptidyl peptidase IV.

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| S-EPMC6821704 | biostudies-literature

Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration.

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| S-EPMC10578189 | biostudies-literature

Dipeptidyl peptidase-4 inhibition to prevent progression of calcific aortic stenosis.

Project description:ObjectiveTo evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression.MethodsOut of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as 'favourable'. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%).ResultsMaximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007).ConclusionsDPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.

| S-EPMC7677484 | biostudies-literature

Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4.

Project description:Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

| S-EPMC6387447 | biostudies-literature

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

Project description:BackgroundDipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.MethodsWe conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.ResultsA total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.ConclusionsIn this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

| S-EPMC7845486 | biostudies-literature

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