Zemiglo Mechanism of Action

Pharmacotherapeutic group: Medicines used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Zemiglo is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which enhances the level of active incretin hormones, including GLP-1 and GIP, thereby reducing blood glucose levels. Active GLP-1 and GIP promote insulin production and release from pancreatic beta cells. GLP-1 also lowers the secretion of glucagon from pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly degraded by the DPP-4. Gemigliptin selectively inhibits DPP-4 activity, enhancing prolonged activation of incretin hormones. Gemigliptin demonstrates >3,400-fold and >9,500-fold selectivity versus DPP-9 and DPP-8, respectively.
Clinical Efficacy and Safety: Over 1,500 patients with type 2 diabetes have been included in randomized, controlled clinical trials. Overall, gemigliptin improved glycemic control when used as monotherapy or in combination treatment.
Gemigliptin dose finding: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase II study of 12 weeks duration. The mean change in HbA1c from baseline at Week 12 was -0.98%, -0.74% and -0.78% (when adjusted with placebo data, -0.92%, -0.68% and -0.72%) at dosage levels of 50 mg, 100 mg and 200 mg, respectively.
Gemigliptin as monotherapy: The efficacy and safety of gemigliptin monotherapy was evaluated in a placebo-controlled Phase III study of 24 weeks duration. The analysis of covariance (ANCOVA) for HbA1c change from baseline at Week 24 (W24 - W0) showed that placebo-subtracted mean HbA1c change from baseline was -0.705% [95% confidence interval (CI) -1.041% to -0.368%]. Therefore, the clinical efficacy of gemigliptin was demonstrated to be superior to that of the placebo group. The study was extended through Week 52. In the extended part of the study, an analysis of HbA1c change from baseline revealed consistent glycemic control effect of gemigliptin over a period of 52 weeks. Further decrease in HbA1c was observed with continued treatment of gemigliptin 50 mg in the latter 28 weeks and the degree of change from baseline at Week 52 (-0.87%) was still clinically and statistically significant (p<0.0001).
Gemigliptin as add-on to metformin therapy: The efficacy and safety of gemigliptin add-on combination therapy were evaluated in an active-controlled Phase III study of 24 week duration. The ANCOVA for HbA1c change from baseline at Week 24 (W24 - W0) showed that the between–group difference (each regimen group of gemigliptin-sitagliptin group) in the least square (LS) mean change from baseline was 0.056% [90% CI -0.117% to 0.23%] for 50 mg qd group and 0.04% [90% CI -0.121% to 0.2%] for 25 mg bid group. Therefore, the clinical efficacy of gemigliptin was demonstrated to be at least comparable with that of the comparator, sitagliptin. The study was extended through Week 52. In the extended part of the study, the change in HbA1c from baseline was clinically and statistically significant (p<0.0001) throughout the duration of 52 weeks in all treatment groups. The decrease in HbA1c was most prominent at Week 6 followed by further gradual decrease thereafter. Decreased HbA1c level was well maintained in all three groups during the extended 28 weeks.
Gemigliptin as add-on to a combination of metformin and sulphonylurea therapy: The efficacy and safety of gemigliptin triple combination therapy with metformin and sulfonylurea were evaluated in a placebo-controlled Phase III study of 24 weeks duration. An ANCOVA was conducted using the HbA1c value at baseline as a covariate and including the glimepiride reduction as a factor in relation to the change in HbA1c at Week 24. In the main population for analysis, the LS mean of the HbA1c change at Week 24 after study treatment was -0.877±0.166% (p<0.0001) in gemigliptin group and -0.012±0.179% (p=0.9476) in the placebo group, showing a significant reduction compared to the baseline in the gemigliptin group. As the 95% CI for the difference in change between the treatment groups was (-1.092%, -0.638%), i.e., its upper limit was less than 0, the superiority of the gemigliptin was demonstrated.
Gemigliptin and metformin as initial therapy: The efficacy and safety of gemigliptin initial combination therapy with metformin were evaluated in an active-controlled Phase III study of 24 weeks duration. For the change of HbA1c from baseline at Week 24, analysis of covariance was performed. As a result, the 95% CI for between group difference in LS means of HbA1c changes in combination therapy group and each monotherapy group were (-1.02%, -0.63%) in combination therapy group compared with gemigliptin group and (-0.82%, -0.41%) in combination therapy group compared with metformin group, respectively. This showed that the upper limits of both CIs were less than zero (p<0.001), confirming superiority of the combination therapy.
Glycemic variability of gemigliptin versus sitagliptin or glimepiride: The efficacy of gemigliptin on MAGE (mean amplitude of glycemic excursions) and safety of initial combination therapy of gemigliptin versus sitagliptin or glimepiride with metformin in patients with type 2 diabetes were evaluated in a multicenter, randomized, active-controlled, parallel group, open-label, exploratory study. The change in MAGE at Week 12 was -43.11 mg/dL, -38.27 mg/dL and -21.74 mg/dL in the gemigliptin and metformin group, sitagliptin and metformin group and glimepiride and metformin group, respectively. As a result of testing the differences between the groups, DPP-4 inhibitors, i.e., the gemigliptin and metformin group and sitagliptin and metformin group, reduced the MAGE compared to sulfonylurea, i.e., glimepiride and metformin group (gemigliptin: p=0.0306, sitagliptin: p=0.0292).
Gemigliptin therapy in patients with renal impairment: The efficacy and safety of gemigliptin monotherapy or its combination therapy with insulin and sulfonylurea in type 2 diabetes patients with moderate or severe renal impairment were evaluated in a double-blind study for 52 weeks duration. The change in HbA1c at Week 12 was -0.96% and 0.21% in the gemigliptin and placebo groups, respectively, showing significant difference between the groups (p<0.0001). Adjusted mean difference between the groups was -1.20% with two sided 95% CI of -1.53 to -0.87%. The upper limit of the 95% CI for the difference in HbA1c change (HbA1c at week 12 - HbA1c at week 0) between groups was lower than 0, which demonstrates the superiority of the gemigliptin over the placebo. The efficacy of gemigliptin was maintained for 52 weeks.
Gemigliptin as add-on to insulin (+/- metformin) therapy: The efficacy and safety of gemigliptin added-on to insulin alone or insulin in combination with metformin in patients with type 2 diabetes were evaluated in a randomized, placebo-controlled, parallel-group, double-blind, phase III study of 24 weeks duration. The primary efficacy endpoint was analysed using an ANCOVA model, with metformin use and country as fixed factors and baseline value as a covariate. In the full analysis set, the LS mean (SE) change from baseline HbA1c after 24 weeks was -0.816% (0.1150%) with gemigliptin and -0.131% (0.1357%) with placebo. The between group difference was -0.685%, and its 95% CI was (-0.941%, -0.429%). The upper limit of the 95% CI for the between group difference in HbA1c changes was less than 0, suggesting superior glycemic control of the gemigliptin compared to the placebo.
The data collected in clinical studies demonstrated that gemigliptin was well tolerated and displayed an overall safety profile that is at least comparable with that of the comparator.
Geriatric: Of the total number of subjects (N=1,473) in Phase II and III clinical studies of gemigliptin, 243 patients (16.5%) were 65 years and over. The efficacy and safety of gemigliptin were not different between young and elderly patients. However, Zemiglo should be used with caution in elderly patient because physiological functions including liver and kidney are usually decreased in this population.
Pharmacokinetics: Absorption: Following a single oral administration of gemigliptin to healthy subjects, gemigliptin was rapidly absorbed, with T_max occurring 1 to 5 hours post-dose. At the recommended dose of 50 mg, C_max and AUC were 62.7 ng/mL and 743.1 ng·hr/mL, respectively. The system exposure was increased in a dose-proportional manner in the range of 50~400 mg.
Distribution: In vitro human plasma protein binding is 29% for gemigliptin and 35%~48% for the metabolites including major active metabolite.
Biotransformation: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In plasma, gemigliptin and the major metabolite (LC15-0636) accounted for 65%~100% and 0%~17.5% of the sample radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, is pharmacologically active and two times more potent than gemigliptin. In vitro studies indicated that gemigliptin is not an inhibitor of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and is not an inducer CYP1A2, 2C8, 2C9, 2C19, or 3A4. Therefore, gemigliptin is considered unlikely to cause interactions with other drugs that utilize these metabolic pathways.
Elimination: Following oral administration of [¹⁴C] gemigliptin to healthy subjects, the administered radioactivity was recovered in feces (27%) or urine (63%). The elimination half-life after oral administration is approximately 17 hr and 24 hr for gemigliptin and LC15-0636, respectively.
Renal Impairment: The influence of renal impairment on the pharmacokinetics of gemigliptin has been evaluated. In patients with mild (CrCl: 50~80 mL/min), moderate (CrCl: 30~50 mL/min), severe (CrCl: <30 mL/min) and end stage renal disease (on hemodialysis), AUC_inf increased 1.20-, 2.04-, 1.50- and 1.69-fold for gemigliptin and 0.91-, 2.17-, 3.07- and 2.66-fold for LC15-0636, when compared with the normal kidney function group. Overall active moiety, the sum of gemigliptin and LC15-0636, was increased less than or approximately 2-fold in patients with moderate and severe renal impairment.
Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of gemigliptin has been evaluated. In mild and moderate hepatic impairment, exposure to gemigliptin (AUC) after single dosing was 50% and 80% higher than in healthy subjects. Formation of LC15-0636, a metabolite of gemigliptin, was only slightly affected by mild hepatic impairment (5% to 10% lower), while in moderate hepatic impairment, formation of LC15-0636 was about 30% lower compared to healthy subjects. Urinary excretion parameters were not markedly influenced by hepatic impairment, so the decrease in total clearance of gemigliptin observed in hepatic impairment is due a decreased metabolization rate of gemigliptin. Half-lives of gemigliptin and of LC15-0636 were slightly increased in hepatic impairment.
In mild and moderate hepatic impairment, inhibition of DPP-4 was slightly decreased compared to healthy subjects (5% to 10%), however, neither the effect on AUEC nor on E_max of DPP-4 inhibition was statistically significant. It is expected that dose adjustment would not be required in mild and moderate hepatic impairment based on the efficacy and safety profile of gemigliptin in clinical and non-clinical studies.
Gender: No dose adjustment is necessary based on gender. The differences in C_max and AUC_inf were not clinically significant.
Race: Caucasian subjects demonstrated 28% decrease in C_max and 5% decrease in AUC_inf when compared with Korean subjects.
Toxicology: Preclinical safety data: A two-year carcinogenicity study was conducted in male and female rats given oral doses of gemigliptin of 50, 150, and 450 mg/kg/day. No evidence of carcinogenicity with gemigliptin was found in either male or female rats. This dose results in exposures approximately 129~170 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 50 mg/day based on AUC comparisons. A 6-month carcinogenicity study has been performed in TgrasH2 transgenic mice at doses of 200, 400, and 800 mg/kg/day in males and 200, 600, 1200 mg/kg/day in females. There was no evidence of carcinogenicity with gemigliptin at a dose of 1200 mg/kg/day, approximately 87 times the human exposure at the maximum recommended daily dose.
Genotoxicity assessments in the Ames test, chromosomal aberrations test and in vivo micronucleus tests in mice and rats were negative.
The fertility of gemigliptin was not affected at dose of 800 mg/kg/day in rat. Gemigliptin was not teratogenic up to 200 mg/kg/day in rats and 300 mg/kg/day in rabbits, which are respectively 83 and 153 times human exposure at the MRHD of 50 mg/day.
Gemigliptin at dose of 800 mg/kg/day in rat, approximately 264 times human exposure at the MRHD of 50 mg/day, increased the incidence of fetus cleft palate malformation, dilated renal pelvis, misshapen thymus and sternoschisis, with increasing dose.