A multicentre, multinational, randomized, placebo‐controlled, double‐blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (<scp>LC15</scp>‐0444) in patients with type 2 diabetes

Yang, Sae Jeong; Min, Kyung-Wan; Gupta, Sandeep K.; Park, J. Y.; Shivane, Vyankatesh; Pitale, Shailesh; Agarwal, Pankaj; Sosale, Aravind; Gandhi, Pramod; Dharmalingam, Mala; Mohan, Viswanathan; Mahesh, Uma; Kim, D. M.; Kim, Y. S.; Kim, J. A.; Kim, P. K.; Baik, Sei-Hyun

doi:10.1111/dom.12042

Cited by 51 publications

(53 citation statements)

References 14 publications

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“…The overall incidence rates for adverse events were similar in the gemigliptin and placebo groups. 89 This study showed the efficacy and safety of gemigliptin 50 mg administered once daily as a monotherapy for T2DM patients.…”

Section: Monotherapymentioning

confidence: 72%

“…Next, a 24-week, randomized, double-blind, placebo-controlled Phase III trial was conducted in 182 patients (74 from Korea and 108 from India) with T2DM. 89 After an initial 2 weeks of a diet and exercise program followed by 2 weeks of a single-blind placebo run-in period, eligible patients were randomized to gemigliptin 50 mg or placebo, receiving the assigned treatment for 24 weeks. HbA 1C and FPG were measured periodically, and oral glucose tolerance test was performed at baseline and weeks 12 and 24.…”

Section: Monotherapymentioning

confidence: 99%

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Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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SUMMARYDipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucoselowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

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Section: Monotherapymentioning

confidence: 72%

Section: Monotherapymentioning

confidence: 99%

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Chen

Zhou

et al. 2015

Clin Exp Pharma Physio

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“…24 In addition, a recently performed phase III study conducted in 182 patients with type 2 diabetes mellitus including Korean and Indian populations also showed that 24 weeks of LC15-0444 treatment at a dose of 50 mg per day led to significant reductions in HbA1c and FPG levels. 25 In a metformin add-on trial performed in 425 Asian patients with inadequately controlled type 2 diabetes being treated with metformin alone, gemigliptin showed comparable efficacy and safety profiles to sitagliptin. 26 In the present study, we observed that the increased urinary excretion of 8-isoprostane after UUO, reflecting the increased oxidative stress in the kidney, was attenuated in mice treated with LC15-0444.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

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Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

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“…Thus, gemigliptin inhibits DPP IV activity, which results in increases in GLP-1 and GIP levels and subsequent insulin responses, eventually improving glycemic control. In clinical studies conducted in Korean subjects with type 2 diabetes, gemigliptin monotherapy (50 mg for 12 weeks) effectively improved glycosylated hemoglobin (HbA1c) level, fasting plasma glucose level, oral glucose tolerance test results, b-cell function and insulin sensitivity measures (Noh et al, 2012;Rhee et al, 2010;Yang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Absorption, distribution, metabolism and excretion of gemigliptin, a novel dipeptidyl peptidase IV inhibitor, in rats

Kim

et al. 2014

Xenobiotica

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1. The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of (14)C-labeled gemigliptin to rats. 2. The (14)C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24 h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples. 3. The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).

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A multicentre, multinational, randomized, placebo‐controlled, double‐blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15‐0444) in patients with type 2 diabetes

Abstract: This study showed the efficacy and safety of gemigliptin 50 mg administered once daily as a monotherapy for type 2 diabetes patients.

Cited by 51 publications

References 14 publications

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Absorption, distribution, metabolism and excretion of gemigliptin, a novel dipeptidyl peptidase IV inhibitor, in rats

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