Inhibitor Report for: Evogliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin(a) (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.

Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.

BACKGROUND: Cardiovascular safety of evogliptin, a novel dipeptidyl peptidase-4 inhibitor (DPP-4i), remains unclear with limited real-world evidence available on its use. We aimed to assess whether the use of evogliptin was associated with an increased risk of cardiovascular events when compared to glimepiride in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a population-based cohort study using South Korea's nationwide healthcare database from 1 January 2014 to 31 December 2018. We identified a base cohort of patients with T2DM who newly initiated metformin monotherapy and from this cohort, identified a study cohort of patients who either added or switched to glimepiride or DPP-4is (including evogliptin). Patients were followed-up from initiation of DPP-4is or glimepiride until the earliest of outcome occurrence or 31 December 2018. Our primary outcome was hospitalization or emergency visit for cardiovascular events, a composite endpoint comprised of cerebrovascular events, heart failure, myocardial infarction, transient ischaemic attack, angina pectoris, and revascularization procedures; secondary outcomes were the individual components of the primary outcome. A multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the risk of study outcomes associated with evogliptin when compared to glimepiride. RESULTS: Our base and study cohorts had 317,307 and 128,788 patients, respectively, of which 100,038 were DPP-4i users (2,946 were evogliptin users) and 28,750 were glimepiride users within the study cohort. The median follow-up was 195 days for evogliptin and 113 days for glimepiride users. Compared with glimepiride, evogliptin was associated with a reduced risk of the primary outcome (aHR 0.67, 95% CI 0.48-0.95) and cerebrovascular events (aHR 0.41, 95% CI 0.22-0.78) but showed non-significant associations for myocardial infarction (aHR 0.63, 95% CI 0.27-1.46), heart failure (aHR 0.35, 95% CI 0.09-1.47), transient ischaemic attack (aHR 0.23, 95% CI 0.03-1.72), and angina pectoris (aHR 1.35, 95% CI 0.82-2.21). CONCLUSIONS: Findings from this population-based cohort study provide novel real-world evidence in that use of evogliptin, as compared with glimepiride, did not increase the risk of cardiovascular events, including cerebrovascular events, myocardial infarction, heart failure, transient ischemic attack, and angina pectoris. This article is protected by copyright. All rights reserved.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin(a) (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.

Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.

AIMS: Evogliptin is a potent and selective dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes mellitus. Since evogliptin is mainly eliminated through hepatic metabolism, we investigated the pharmacokinetics (PKs) and safety characteristics of evogliptin in Korean patients with mild or moderate hepatic impairment. METHODS: An open-label, parallel-group study was conducted in patients with mild or moderate hepatic impairment and healthy control subjects matched to each patient for sex, age and body mass index. A single dose (5 mg) of evogliptin was administered orally, and serial blood samples were collected over 120 h to assess the PK profile of evogliptin and its main metabolites (M7 and M8). RESULTS: Patients with mild hepatic impairment and their matched healthy controls showed similar maximum concentration (C(max) ) and area under the concentration-time curve values from 0 to 120 h (AUC(last) ); the geometric mean ratio (GMR) and 90% confidence interval (CI) were 1.04 (0.80, 1.35) and 1.01 (0.90, 1.14), respectively. Exposure to evogliptin (C(max) and AUC(last) ) was increased by about 40% in patients with moderate hepatic impairment-the GMR and 90% CI were 1.37 (1.09, 1.72) and 1.44 (1.18, 1.75), respectively. The metabolic ratios of M7 and M8 were lower in patients with moderate hepatic impairment than in matched healthy controls. Evogliptin was well tolerated by both patients and healthy subjects. CONCLUSION: Although evogliptin exposure was increased in patients with moderate hepatic impairment, the increase is unlikely to affect safety and efficacy adversely, and no dose adjustment is warranted.

BACKGROUND: Cardiovascular safety of evogliptin, a novel dipeptidyl peptidase-4 inhibitor (DPP-4i), remains unclear with limited real-world evidence available on its use. We aimed to assess whether the use of evogliptin was associated with an increased risk of cardiovascular events when compared to glimepiride in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a population-based cohort study using South Korea's nationwide healthcare database from 1 January 2014 to 31 December 2018. We identified a base cohort of patients with T2DM who newly initiated metformin monotherapy and from this cohort, identified a study cohort of patients who either added or switched to glimepiride or DPP-4is (including evogliptin). Patients were followed-up from initiation of DPP-4is or glimepiride until the earliest of outcome occurrence or 31 December 2018. Our primary outcome was hospitalization or emergency visit for cardiovascular events, a composite endpoint comprised of cerebrovascular events, heart failure, myocardial infarction, transient ischaemic attack, angina pectoris, and revascularization procedures; secondary outcomes were the individual components of the primary outcome. A multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the risk of study outcomes associated with evogliptin when compared to glimepiride. RESULTS: Our base and study cohorts had 317,307 and 128,788 patients, respectively, of which 100,038 were DPP-4i users (2,946 were evogliptin users) and 28,750 were glimepiride users within the study cohort. The median follow-up was 195 days for evogliptin and 113 days for glimepiride users. Compared with glimepiride, evogliptin was associated with a reduced risk of the primary outcome (aHR 0.67, 95% CI 0.48-0.95) and cerebrovascular events (aHR 0.41, 95% CI 0.22-0.78) but showed non-significant associations for myocardial infarction (aHR 0.63, 95% CI 0.27-1.46), heart failure (aHR 0.35, 95% CI 0.09-1.47), transient ischaemic attack (aHR 0.23, 95% CI 0.03-1.72), and angina pectoris (aHR 1.35, 95% CI 0.82-2.21). CONCLUSIONS: Findings from this population-based cohort study provide novel real-world evidence in that use of evogliptin, as compared with glimepiride, did not increase the risk of cardiovascular events, including cerebrovascular events, myocardial infarction, heart failure, transient ischemic attack, and angina pectoris. This article is protected by copyright. All rights reserved.

AIMS: This trial consisted of a 24-week multicentre, randomized, double-blind, double-dummy, active-controlled study and a 52-week open label extension study to assess the efficacy and safety of evogliptin, a novel dipeptidyl peptidase-4 inhibitor, compared to sitagliptin in patients with type 2 diabetes who have inadequate glycaemic control with metformin alone.
METHODS: Adult patients with type 2 diabetes mellitus (N = 222) with HbA1c 6.5% to 11% who were receiving stable doses of metformin (>/=1000 mg/d) were randomized 1:1 to add-on evogliptin 5 mg (N = 112) or sitagliptin 100 mg (N = 110) once daily for 24 weeks. The primary efficacy analysis consisted of a comparison of the change from baseline HbA1c at week 24. Non-inferiority was concluded if the upper limit of the 2-sided 95% confidence interval for the HbA1c difference between treatments was <0.35%.
RESULTS: Mean changes in HbA1c following addition of evogliptin or sitagliptin were -0.59% and -0.65%, respectively. The between-group difference was 0.06% (2-sided 95% confidence interval, -0.10 to 0.22), demonstrating non-inferiority. After the 52-week treatment, evogliptin caused a persistently decreased level of HbA1c (-0.44% +/- 0.65%, P < .0001). In general, both treatments were well tolerated, with incidences and types of adverse events comparable between the two groups. Hypoglycaemic events, mostly mild, were reported in 0.9% of patients treated with evogliptin and in 2.8% of patients treated with sitagliptin for 24 weeks.
CONCLUSIONS: Evogliptin 5 mg added to metformin therapy effectively improved glycaemic control and was non-inferior to sitagliptin and well tolerated in patients with type 2 diabetes mellitus that was inadequately controlled by metformin alone.

Dipeptidyl peptidase 4 (DPP4) is an adipokine that interrupts insulin signaling. The resulting insulin resistance exacerbates hepatic steatosis. We previously reported that the novel DPP4 inhibitor evogliptin improves insulin resistance. This study aimed to verify the therapeutic potential of evogliptin for fatty liver. Evogliptin treatment was initiated simultaneously with a high-fat diet (HFD) feeding in normal mice and in a post-24 week HFD-fed rats. In a prevention study, insulin sensitivity was preserved in evogliptin-treated mice after a 16-week treatment. Overall plasma lipid levels stayed lower and hepatic lipid accumulation was drastically suppressed by evogliptin treatment. Evogliptin reduced hepatic expression of Srebf1, a key transcriptional factor for lipogenesis. Additionally, DPP4 inhibitor-treated mice showed less weight gain. In a treatment study, after evogliptin treatment for 14 weeks in pre-established HFD-fed obese rats, weight loss was marginal, while hepatic lipid accumulation and liver damage assessed by measuring plasma aminotransferase levels were completely resolved, suggesting weight loss-independent beneficial effects on fatty liver. Moreover, reduction in plasma non-esterified fatty acids supported the improvement of insulin resistance by evogliptin treatment. Conclusively, our findings suggest that evogliptin treatment ameliorates fatty liver by increasing insulin sensitivity and suppressing lipogenesis.

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (S,R diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S1 pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S2 extensive subsite, and that the multiple hydrogen bonds made by the (R)-beta-amine group in the S2 pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin.

To date, little is known about the transporter-mediated drug-drug interaction (DDI) potential of evogliptin, a novel DPP-4 inhibitor. The objective of this study was to evaluate the DDI potential of evogliptin using various in vitro assays in transporter-expressing cell lines. After incubating evogliptin with cells overexpressing OAT1, OAT3, OCT2, OATP1B1 and OATP1B3, there was no notable cellular accumulation of evogliptin (fold accumulation, 0.41-1.86). In bidirectional transport assays using a Caco-2 cell monolayer, a high efflux ratio (ER, 522) of evogliptin was observed, which was significantly decreased (97.96%) in the presence of a potent P-gp inhibitor. In assays using MDCKII-BCRP cell monolayers, by contrast, a low net ER (1.16-1.26) was found. In similar cellular uptake and bidirectional studies with probe substrates of P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3, the active transport of the substrates was not significantly suppressed by evogliptin. These results suggest that evogliptin may be a substrate of P-gp, but not a substrate of BCRP, OAT1B1, OAT1B3, OAT1, OAT3 or OCT2, and not an inhibitor of any of these transporters. Therefore, it could be concluded that evogliptin has some DDI potential involving P-gp, but it has low potential of DDI mediated by the other transporters.

Evogliptin is a novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin in participants with renal impairment (RI). An open-label, parallel-group clinical study was conducted in participants with mild, moderate and severe RI and in matched participants with normal renal function (NRF). A single oral 5-mg dose of evogliptin was administered and serial blood and urine samples were obtained to assess the PK and PD characteristics of evogliptin. Baseline urine samples were collected to evaluate endogenous CYP3A metabolic markers. The plasma exposure to evogliptin and degree of DPP-4 activity inhibition increased with decreasing renal function. The mean areas under the concentration-time curves from 0 to 120 hours were increased 1.2-, 1.8- and 1.98-fold in the mild, moderate and severe RI groups, respectively, compared with the NRF group. The levels of CYP3A metabolic markers were lower in the RI group than in the NRF group. The increase in the plasma concentration of evogliptin is unlikely to result in changes in its efficacy or safety, considering the results of previous clinical studies.

WHAT IS KNOWN AND OBJECTIVE: Evogliptin (DA-1229), a novel dipeptidyl peptidase (DPP)-4 inhibitor with high potency and selectivity, was approved in Korea for the treatment of type 2 diabetes. Preclinical studies suggest that it is metabolized by cytochrome (CYP) P450 isozymes. Based on these findings, a clinical study was designed to investigate the pharmacokinetic (PK) interaction of evogliptin with a CYP inhibitor, clarithromycin. METHODS: An open-label, two-phase, crossover study was conducted with 12 healthy subjects. On day 1, a single dose of evogliptin 5 mg was administered alone to assess the reference PK profile of evogliptin. On day 10, after a 2-day pretreatment with clarithromycin, evogliptin 5 mg was administered again to evaluate the effect of CYP inhibition on the PK profile of evogliptin. Administration of clarithromycin continued until day 14. Blood sampling in the reference and test phases was performed until 96 and 168 hours after dosing, respectively for PK assays. RESULTS: Eleven of the 12 subjects completed the study, and their data were analysed. In the presence of clarithromycin, exposure to evogliptin increased without any serious adverse events and the geometric mean peak plasma concentration (Cmax ) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity ) of evogliptin increased by 116.5% and 89.6%, respectively. WHAT IS NEW AND CONCLUSION: Administration of clarithromycin significantly increased exposure to evogliptin in healthy subjects.

AIMS: To evaluate the efficacy and safety of evogliptin, a newly developed dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes (T2D) inadequately controlled by diet and exercise. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, multicentre, phase III study, 160 patients with T2D were assigned to either evogliptin 5 mg or placebo for 24 weeks. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) from baseline to week 24. RESULTS: The mean baseline HbA1c levels were similar in the evogliptin and the placebo groups (7.20% +/- 0.56% vs 7.20% +/- 0.63%, respectively). At week 24, evogliptin significantly reduced HbA1c levels from baseline compared with placebo (-0.23% vs 0.05%, respectively, P < .0001). Additionally, the proportion of patients achieving HbA1c <6.5% was significantly higher in the evogliptin group than in the placebo group (33.3% vs 15.2%; P = .008). The overall incidence of adverse events, including hypoglycaemia, was similar in the 2 groups. CONCLUSIONS: In this 24-week study, once-daily evogliptin monotherapy significantly improved glycaemic control and was well tolerated in patients with T2D.

OBJECTIVES: The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations).
METHODS: A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including C_max and AUC_last were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the C_max and AUC_last of evogliptin and metformin.
RESULTS: 33 subjects completed the study. The GMR (90% CI) values of C_max and AUC_last for evogliptin were 1.011 (0.959 - 1.066) and 1.010 (0.977 - 1.043), respectively. The GMR (90% CI) values of C_max and AUC_last for metformin were 0.892 (0.827 - 0.963) and 0.893 (0.841 - 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment.
CONCLUSIONS: Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 - 1.250..

Although multiple dipeptidyl peptidase 4 (DPP4) inhibitors have shown glucose-lowering effects by preserving pancreatic cells in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, the hepatic role in regulation of glucose homeostasis by DPP4 inhibitors in HFD/STZ mice remains elusive. In herein study, parallel comparison of effects on the liver (expression of gluconeogenic genes and the linked signaling molecules) and pancreas (islet morphology and relative area of alpha or beta cells) in combination with glucose-lowering effects were made at the end of 2- and 10-week of evogliptin treatment in HFD/STZ mice. Significant control of hyperglycemia was observed from the second week and persisted during 10-week treatment of 0.3% evogliptin in HFD/STZ mice. This effect was accompanied by increased level of plasma glucagon-like peptide-1 and preserved pancreas islet structure. Furthermore, the hepatic increases in gluconeogenic gene expression in HFD/STZ mice was significantly reduced by evogliptin treatment, which was accompanied by the suppression of cAMP response element-binding protein (CREB) phosphorylation and expression of transducer of regulated CREB protein 2. This hepatic effect of evogliptin treatment was reproduced in 2-week study, however, pancreatic beta-cell area was not altered yet although the expression of pancreatic and duodenal homeobox protein 1 was increased. We conclude that the suppression of hepatic gluconeogenesis by evogliptin is followed by preservation of pancreatic islet, leading to remarkable and persistent glucose-lowering effect in HFD/STZ mice. Our findings provide further insight for the hepatic role in DPP4 inhibitor-mediated glucose control in diabetes.

A new fixed-dose combination formulation of evogliptin 5 mg and metformin extended-release (XR) 1,000 mg (FDC_EVO5/MET1000) was developed to improve medication adherence for type 2 diabetes mellitus. The pharmacokinetics of FDC_EVO5/MET1000 was compared to the corresponding loose combination in a randomized, open-label, crossover study in 36 healthy male subjects (Part 1), and the food effect on FDC_EVO5/MET1000 was assessed (under fasted or fed conditions) in a randomized, open-label, crossover study in 28 healthy male subjects (Part 2). Serial blood samples for pharmacokinetic analysis were collected up to 72 hours, and pharmacokinetic parameters of evogliptin and metformin were calculated using non-compartmental methods. The geometric mean ratios (fixed-dose combination to loose combination) and 90% confidence intervals of pharmacokinetic parameters for evogliptin and metformin were all within 0.800-1.250, suggesting bioequivalent pharmacokinetic. After a single oral dose of FDC_EVO5/MET1000, food did not significantly affect evogliptin pharmacokinetic while systemic exposure of metformin was increased about 47.5% under the fed condition, which is consistent with the already established food effect on metformin XR. FDC_EVO5/MET1000 was generally well tolerated without any drug-related serious adverse events. In conclusion, FDC_EVO5/MET1000 can be substituted for the loose combination of FDC_EVO5/MET1000, providing better compliance with convenient administration.

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 type 2 diabetes mellitus.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon(TM)) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise. AREAS COVERED: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed. EXPERT OPINION: Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and beta-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)-pipe razin-2-one), is a new dipeptidyl peptidase IV inhibitor used for the treatment of type II diabetes mellitus. The in vitro metabolic pathways of evogliptin were identified in human hepatocytes, liver microsomes, and liver S9 fractions using liquid chromatography-Orbitrap mass spectrometry (LC-HRMS). Five metabolites of evogliptin-4-oxoevogliptin (M1), 4(S)-hydroxyevogliptin (M2), 4(R)-hydroxyevogliptin (M3), 4(S)-hydroxyevogliptin glucuronide (M4), and evogliptin N-sulfate (M5)-were identified in human liver preparations by comparison with authentic standards. We characterized the cytochrome P450 (CYP) enzymes responsible for evogliptin hydroxylation to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3) and the UGT enzymes responsible for glucuronidation of 4(S)-hydroxyevogliptin (M2) to 4(S)-hydroxy-evogliptin glucuronide (M4). CYP3A4/5 played the major role in the hydroxylation of evogliptin to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3). Glucuronidation of 4(S)-hydroxy-evogliptin (M2) to 4(S)-hydroxyevogliptin glucuronide (M4) was catalyzed by the enzymes UGT2B4 and UGT2B7. These results suggest that the interindividual variability in the metabolism of evogliptin in humans is a result of the genetic polymorphism of the CYP and UGT enzymes responsible for evogliptin metabolism.

Evogliptin (Suganon) is an orally bioavailable, selective dipeptidyl peptidase-4 (DPP-4; CD26 antigen) inhibitor being developed by Dong-A ST for the treatment of type 2 diabetes mellitus. DPP-4 inhibitors control glucose levels by preventing the breakdown of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which stimulate insulin secretion in response to the increased levels of glucose in the period following meals. In October 2015, evogliptin received its first global approval in South Korea for blood glucose control in patients with type 2 diabetes mellitus. This article summarizes the milestones in the development of evogliptin leading to this first approval for type 2 diabetes mellitus.

PURPOSE: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects. PATIENTS AND
METHODS: A block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin's pharmacodynamics on the first and last dosing days.
RESULTS: All participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4-5 hours and decreased relatively slowly, with a terminal elimination half-life of 33-39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin's systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%-35% compared to placebo, but were not accompanied by increased insulin levels. CONCLUSION: Repeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5-20 mg dose range. A once-daily regimen of 5-20 mg evogliptin effectively inhibited DPP-IV activity.