Zemimet SR Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs. ATC code: A10BD18.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Zemimet SR combines two anti-hyperglycemic medicinal products with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: gemigliptin tartrate sesquihydrate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Gemigliptin: Mechanism of Action: Gemigliptin is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which enhance 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 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 2,200 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 week 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 multinational, multicenter, randomized, placebo-controlled, parallel group, double-blind, 24-week study. The mean HbA1c change from baseline at Week 24 was -0.64% for this drug and 0.08% for placebo. The difference in HbA1c change compared to placebo was -0.71% (95% CI: -1.04, -0.37), which was a statistically significant decrease (p-value <0.0001).
Gemigliptin as add-on to metformin therapy: A multicenter, multinational, randomized, active-controlled, parallel group, double-blind, 24-week trial was conducted to evaluate the efficacy and safety of gemigliptin 50 mg compared with sitagliptin 100 mg added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin (≥1,000 mg/day) alone. Gemigliptin 50 mg once daily, gemigliptin 25 mg twice daily, or sitagliptin 100 mg once daily were administered, and after 24 weeks, the mean difference in HbA1c change from baseline was -0.87% for gemigliptin 50 mg (25 mg twice daily), -0.82% for gemigliptin 50 mg, and -0.92% for sitagliptin 100 mg. The difference in HbA1c change compared to sitagliptin was 0.06% (90% CI upper limit: 0.23) (50 mg once daily) and 0.04% (90% CI upper limit: 0.20) (25 mg twice daily), demonstrating non-inferiority (non-inferiority margin: 0.4).
Gemigliptin as add-on to a combination of metformin and sulfonylurea therapy: A multicenter, randomized, placebo-controlled, parallel group, double-blind, 24-week trial was conducted to evaluate the efficacy and safety of added gemigliptin 50 mg qd in patients with type 2 diabetes inadequately controlled with a combination therapy of metformin (≥1,000 mg/day) and glimepiride (≥4 mg/day or maximum tolerated dose). After 24 weeks, the mean change in HbA1c from baseline was -0.73% and 0.14% in the gemigliptin and placebo groups, respectively. The difference in HbA1c change compared to placebo was -0.87% (95% CI: -1.09, -0.64), which was a statistically significant decrease (p-value <0.0001).
Gemigliptin as add-on to insulin (+/- metformin) therapy: A multinational, multicenter, randomized, placebo-controlled, parallel group, double-blind, 24-week trial was conducted to evaluate the efficacy and safety of added gemigliptin 50 mg compared with added placebo in subjects with type 2 diabetes who have inadequate glycemic control on insulin alone or on insulin in combination with metformin (≥1,000 mg/day). After 24 weeks, the mean change in HbA1c from baseline was -0.77% and -0.08% in the gemigliptin and placebo groups, respectively. The difference in HbA1c change compared to placebo was -0.69% (95% CI: -0.94, -0.43), which was a statistically significant decrease (p-value <0.0001).
Gemigliptin and metformin as initial therapy: The efficacy and safety of this product were evaluated in a multinational, multicenter, randomized, active-controlled, parallel-group, double-blind, 24-week trial in which gemigliptin 50 mg and metformin (≥500 mg) were administered once daily to patients with type 2 diabetes with poor glycemic control. The mean change in HbA1c compared to baseline after 24 weeks was -2.06% in the combination group and -1.24% and -1.47% in the gemigliptin 50 mg and metformin monotherapy group, respectively. The change in HbA1c when compared to each single agent was statistically significant (p-value <0.0001) at -0.82% (95% CI: -1.02, -0.63) for gemigliptin monotherapy and -0.62% (95% CI: -0.82, -0.41) for metformin monotherapy.
Gemigliptin as add-on to dapagliflozin and metformin therapy: A multicenter, randomized, placebo-controlled, parallel group, double-blind, 24-week study to evaluate the efficacy and safety of added gemigliptin 50 mg or placebo once daily in patients with type 2 diabetes who have inadequate glycemic control with dapagliflozin (10 mg/day) and metformin (≥1,000 mg/day). After 24 weeks, the mean change in HbA1c from baseline was -0.86% and -0.20% in the gemigliptin and placebo groups, respectively. The difference in HbA1c change compared to placebo was -0.66% (95% CI: -0.80, -0.52), which was a statistically significant decrease (p-value <0.0001).
Metformin: Mechanism of action: Metformin is a biguanide with anti-hyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via three mechanisms: by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilization; by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
In humans, independently of its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
Clinical efficacy and safety: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034; a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017; a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021); a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
Pharmacokinetics: Zemimet SR: A bioequivalence study in healthy subjects demonstrated that the Zemimet SR (gemigliptin/metformin hydrochloride) combination tablets are bioequivalent to co-administration of gemigliptin and metformin hydrochloride as individual tablets.
The effects of food on pharmacokinetics of Zemimet SR (gemigliptin/metformin hydrochloride) combination tablets were similar to the known food effects of gemigliptin or metformin as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of Zemimet SR.
Gemigliptin: 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 the 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 9%~18% 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 to 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.
Geriatric: Of the total number of patients (N=1473) in Phase II and III clinical studies, 243 (16.5%) were 65 years and over. The efficacy and safety of gemigliptin were not different between young and elderly patients. However, Zemimet SR should be used with caution in elderly patients because physiological functions including liver and kidney are usually decreased in this population.
Metformin: Absorption: After an oral dose of metformin, T_max is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/mL. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 µg/mL, even at maximum doses.
Interaction with food: Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean V_d ranged between 63-276 L.
Biotransformation: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Toxicology: Preclinical safety data: No animal studies have been conducted with Zemimet SR. Potential toxicity and reversibility to the combination of gemigliptin and metformin was evaluated in rats administered co-suspended formulation.
In the oral rat single-dose study, the approximate lethal dose levels were considered to be greater than 150 mg/kg and 1,500 mg/kg for gemigliptin and metformin, respectively.
In 3-month toxicity studies in which rats were treated with either metformin or gemigliptin alone, or a combination of metformin and gemigliptin, no additional toxicity was observed from the combination. The NOAEL in these studies was observed at exposures to gemigliptin of approximately 23~26 times the human exposure (50 mg) and to metformin of approximately 13~14 times the human exposure (1,000 mg).
The following data are findings in studies performed with gemigliptin or metformin individually.
Gemigliptin: 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 1,200 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 rats.
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 rats, 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.
Metformin: Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.