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Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor β (TGF-β) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-β. In addition, evogliptin inhibited TGF-β-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy.

Dipeptidyl-peptidase IV (DPP4) inhibitors have shown potential anti-tumor properties. This study investigates the therapeutic potential of evogliptin, a DPP4 inhibitor, both as a single agent and in combination with temozolomide (TMZ), in glioma models. In vitro studies were performed using U87 and U373 glioma cell lines exposed to different concentrations of TMZ (250, 500 μM) and evogliptin (250, 500 ng/mL), either alone or together, for 24, 48, and 72 h. Cell viability was determined with the MTT assay. In vivo effectiveness was tested in a xenograft mouse model treated with intraperitoneal injections of evogliptin (60 mg/k g/day), TMZ (15 mg/kg/day), or their combination over 3 weeks. The combination of TMZ and evogliptin markedly reduced cell viability compared to single-agent treatments. DPP4 mRNA levels decreased more substantially with combination therapy. miRNA expression profiling with Affymetrix arrays indicated that certain miRNAs, such as miR-4440 and miR-6780b-5p, were upregulated after treatment with evogliptin or the combination regimen, whereas others were downregulated. These miRNAs could play a role in limiting glioma growth through DPP4 regulation. In the animal model, evogliptin alone did not provide a survival advantage. Analysis of TCGA data showed that glioma patients with decreased DPP4 expression had improved survival rates. The co-administration of evogliptin and temozolomide resulted in distinct miRNA profile changes. Nevertheless, both in vitro and in vivo, the added cytotoxicity from the combination was minimal.

Evogliptin is one of the latest dipeptidyl peptidase-4 (DPP-4) inhibitor, and a number of clinical trials have been performed following its development, including several randomized controlled trials (RCTs) performed to evaluate its efficacy and tolerability. In our study, we performed a systematic review and meta-analysis of its efficacy and tolerability by collecting RCTs and confirmed the results with Bayesian inference. Moreover, an updated quality-management system was integrated into the study process of systematic review. PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for literature published between May 1990 and November 2020. We selected 6 homogeneous RCTs in 1017 subjects for efficacy and 1070 subjects for tolerability analysis. Regarding the efficacy profile, the mean differences from baseline (95% CIs) in hemoglobin (Hb) A1c and fasting plasma glucose (FPG) were generated as end points and derived from each study. Regarding the tolerability profile, risk ratios of adverse events (AEs), serious AEs, adverse drug reactions, and hypoglycemia were generated from baseline to outcome measurements as derived from each study. A subsequent meta-analysis was performed with Bayesian inference. For HbA1c and FPG, the results suggested a statistically significant improvement with evogliptin versus placebo (HbA1c, −0.44 [95% CI, −0.54 to −0.34; P < 0.00001] and posterior median, −0.38 [95% CI, −0.51 to −0.24]; FPG, −0.61 [95% CI, −0.90 to −0.31; P < 0.0001] and posterior median, −0.48 [95% CI, −0.90 to −0.16]), but no statistically significant difference with evogliptin versus other DPP-4 inhibitors (HbA1c, −0.01 [95% CI, −0.14 to 0.12] and posterior median, −0.06 [95% CI, −0.25 to 0.12]; FPG, 0.17 [95% CI, −0.10 to 0.44] and posterior median, 0.27 [95% CI, −0.12 to 0.65]). In terms of tolerability, the overall prevalence of adverse events, including hypoglycemia, was similar between evogliptin and other DPP-4 inhibitors and placebo. Evogliptin appears more efficacious in terms of changes in HbA1c and FPG compared with placebo, with an efficacy comparable to those of other DPP-4 inhibitors, although with the limited data studied and the minuscule sample sizes, the predictions of posterior medians, mean differences, and risk ratios of HbA1c, FPG, and AEs by Bayesian inference were consistent with our findings through our quality-management system. [Display omitted]

Background A quality by design approach can potentially lead to a more robust/rugged method development due to emphasis on the risk assessment and management. By carefully understanding the step-by-step procedure for analytical QbD-based optimization parameters, such as analytical target profile and critical quality attributes (CQAs), was assessed. The present study describes the simple, rapid, sensitive and cost-effective RP-HPLC method development and validation for the estimation of evogliptin tartrate in pharmaceutical dosage form. Results The factor screening studies were performed using Box–Behnken design by three key components of the RP-HPLC method (mobile phase, pH and flow rate). The chromatographic conditions were optimized with the Design Expert software trial version 13.0. The optimal chromatographic separation was achieved having water C18 column (250 mm × 4.6 mm, 5 μ) and using mobile phase as a methanol and phosphate buffer (pH 4.5) 60:40% v/v with a flow rate 1.0 ml/min and UV detection at 267 nm. The Box–Behnken experimental design describes the interrelationship of mobile phase, pH and flow rate at three different levels, and responses of retention time and tailing factor were observed with response surface plot and statistical data. The developed method was validated as per recommended ICH guidelines which revealed the high degree of linear, precise, accurate, sensitive and robust method over the existing RP-HPLC method for evogliptin tartrate. Conclusion The developed QbD-based method helped in generating a design space and operating space with knowledge of all method performance characteristics, and RP-HPLC method takes less time and can be used in the industry for routine quality control of bulk and marketed formulation of evogliptin tartrate.

There are few studies on the effects of dipeptidyl peptidase-4 inhibitors on steatohepatitis. We explored whether evogliptin (Evo), a dipeptidyl peptidase-4 inhibitor, protects against steatohepatitis in a high-fat diet (HFD)-fed mice and whether these effects involve modulation of mitophagy. Adult male C57BL/J mice were divided into the normal diet (ND), HFD (45% of energy from fat) with Evo (250 mg/kg) (HFD + Evo), and HFD groups at 4 weeks of age and were sacrificed at 20 weeks of age. The HFD group showed hepatic lipid accumulation; this was decreased in the Evo + HFD group. There was an increased 8-hydroxydeoxyguanosine (8-OHDG) expression in the HFD group compared to ND mice. However, 8-OHDG expression levels were significantly decreased in the HFD + Evo group. Expressions of the mitophagy markers PTEN-induced kinase 1 (PINK1), Parkin, and BNIP-3 (BCL2 Interacting Protein 3) were significantly increased in the HFD group. However, the expressions of these markers were lower in the HFD + Evo group than that in the HFD group. Phospho-Akt was upregulated and p53 was downregulated in the HFD + Evo group compared to the HFD group. Evogliptin may alleviate steatohepatitis in HFD-fed mice by ameliorating steatosis and oxidative stress and by modulating mitophagy in the liver.

Su-jin Rhee,1,* YoonJung Choi,1,* SeungHwan Lee,1,2 Jaeseong Oh,1 Sung-Jin Kim,3 Seo Hyun Yoon,1 Joo-Youn Cho,1 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; 2Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea; 3Department of Clinical Development, Dong-A ST Co., Ltd., Seoul, Republic of Korea *These authors contributed equally tothis work Abstract: Evogliptin is a newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which is expected to be combined with metformin for treating type 2 diabetes mellitus. We investigated the potential pharmacokinetic and pharmacodynamic interactions between evogliptin and metformin. A randomized, open-label, multiple-dose, six-sequence, three-period crossover study was conducted in 36 healthy male subjects. All subjects received three treatments, separated by 7-day washout intervals: evogliptin, 5 mg od for 7 days (EVO); metformin IR, 1,000 mg bid for 7 days (MET); and the combination of EVO and MET (EVO + MET). After the last dose in a period, serial blood samples were collected for 24 hours for pharmacokinetic assessments. During steady state, serial blood samples were collected for 2 hours after an oral glucose tolerance test, and DPP-4, active glucagon-like peptide-1, glucose, glucagon, insulin, and C-peptide were measured to assess pharmacodynamic properties. EVO + MET and EVO showed similar steady state maximum concentration and area under the concentration-time curve at steady state values for evogliptin; the geometric mean ratios (90% confidence interval) were 1.06 (1.01-1.12) and 1.02 (0.99-1.06), respectively. EVO + MET slightly reduced steady state maximum concentration and area under the concentration-time curve at steady state values for metformin compared to MET, with geometric mean ratios (90% confidence interval) of 0.84 (0.79-0.89) and 0.94 (0.89-0.98), respectively. EVO + MET and EVO had similar DPP-4 inhibition efficacy, but EVO + MET increased active glucagon-like peptide-1 and reduced glucose to larger extents than either EVO or MET alone. Our results suggested that EVO+MET could provide therapeutic benefits without clinically significant pharmacokinetic interactions. Thus, the EVO + MET combination is a promising option for treating type2 diabetes mellitus. Keywords: type 2 diabetes, drug interaction, DA-1229, DPP-4 inhibitor, OGTT

Aims: No meta-analysis is available which has summarized and holistically analyzed the efficacy and safety of evogliptin. We undertook this meta-analysis to address this gap in knowledge Methods: Electronic databases were searched for RCTs involving diabetes patients receiving evogliptin in intervention arm and placebo/active comparator in control arm. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in fasting glucose, postprandial glucose, lipids, insulin resistance, patients achieving glycemic targets of HbA1c <7% and <6.5%, and adverse events. Results: From initially screened 57 articles, data from six RCTs involving 887 patients was analyzed [three having sitagliptin/linagliptin as active comparator; three having placebo in control group]. Evogliptin was noninferior to sitagliptin/linagliptin regarding HbA1c reduction at 12 weeks [mean difference (MD) -0.06%; 95%CI: -0.23-0.11%; P = 0.48] and 24 weeks (MD 0.04%; 95%CI: -0.11-0.19%; P = 0.60) follow-up. Evogliptin was superior to placebo regarding HbA1c reduction at 12-weeks (MD -0.57%; 95%CI: -0.62- -0.52%; P < 0.001) and 24 weeks (MD -0.28%; 95%CI: -0.47 - -0.09%; P = 0.004). Evogliptin was noninferior to sitagliptin/linagliptin regarding patients achieving HbA1c <7% and <6.5% at 12 weeks and 24 weeks follow-up. Total adverse events [Risk ratio (RR) 0.98; 95% CI: 0.72-1.32; P = 0.89] and severe adverse events (RR 0.65; 95% CI: 0.25-1.67; P = 0.37) were not significantly different among groups. Patients receiving evogliptin did not have increased symptomatic (RR 0.46; 95% CI: 0.10-2.16; P = 0.32) and asymptomatic (RR 1.09; 95% CI: 0.61-1.97; P = 0.77) hypoglycaemia. Conclusion: Evogliptin is well tolerated and has good glycemic efficacy over 6 months use for T2DM management

Background: Evogliptin tartrate inhibits dipeptidyl peptidase-4 (DPP-4), boosting glucagon-like peptide 1 (GLP-1) secretion and improving insulin release and glucose tolerance, while also exerting anti-inflammatory effects. We investigated its anti-inflammatory and analgesic effects. Methods: Forty male Sprague Dawley rats were divided into (N = 10 in each): (1) naïve, (2) complete Freund’s adjuvant (CFA) inflammation + evogliptin tartrate (once for 10 mg/kg) (CFAE), (3) CFA + vehicle (same volume with normal saline with evogliptin tartrate/once) (CFAV), and (4) CFA + indomethacin (5 mg/mL/kg/1 time) (CFAI) groups. CFA was injected subcutaneously into rat plantar regions, and medications (evogliptin tartrate, vehicle, and indomethacin) were administered orally for 5 days. Post treatment, blood from the heart and plantar inflammatory tissue were collected to assess inflammatory cytokines. Evogliptin tartrate effects on controlling inflammation and pain were evaluated by measuring rat plantar paw thickness, paw withdrawal threshold, dorsal root ganglion (DRG) resting membrane potential, DRG action potential firing, and cytokine (TNF-α and IL-1β) levels. Results: Compared with the naïve group, plantar paw thickness, cytokine (TNF-α and IL-1β) levels, DRG resting membrane potential, and DRG action potential firing increased, whereas the paw withdrawal threshold decreased in all CFA groups. However, CFAE and CFAI rats showed recovery. The degree of CFAE recovery resembled that observed in the CFAI group. Conclusions: Evogliptin tartrate mirrored the anti-inflammatory pain relief of indomethacin. We aim to broaden its use as an anti-inflammatory drug or pain relief drug.

Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics. An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference. Maximum concentration (C ) and area under the plasma drug concentration-time curve (AUC ) of evogliptin with and without co-administration of rifampicin were compared. Reference and test C and AUC values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration. Rifampicin decreased the AUC of evogliptin by 61.8% without significantly affecting C . The mechanism underlying the decrease in AUC is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.

Background Evogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO’s clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg). Methods In this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12—baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < − 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned. Results HbA1c mean reductions were − 1.26% (90% CI − 1.7%, − 0.8%), − 1.12% (90% CI − 1.4%, − 0.8%), − 1.29% (90% CI − 1.6%, − 1.0%), and − 1.15% (90% CI − 1.5%, − 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of − 18.94 mg/dL, − 21.17 mg/dL, and − 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO’s “target” dose (5 mg) was confirmed. No safety concerns were identified. Conclusions These results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg). Trial registration ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016).