Zemidapa Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs. ATC code: A10BD30.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Gemigliptin/Dapagliflozin 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 DPP-4 inhibitor, and dapagliflozin, a SGLT 2 inhibitor.
Clinical efficacy and safety: Glycemic control: Gemigliptin add-on to metformin and dapagliflozin combination therapy: In a 24-week, multicenter, randomized, placebo-controlled, parallel-group, double-blind study, gemigliptin 50 mg was compared to placebo once daily as add-on therapy in subjects with inadequate glycemic control type 2 diabetes mellitus (7.0% ≤ HbA1c ≤ 11.0%) in combination with metformin (≥1,000 mg/day) and dapagliflozin (10 mg/day).
At week 24, the adjusted mean change in HbA1c from baseline was -0.86% for the gemigliptin 50 mg group and -0.20% for the placebo group. Gemigliptin 50 mg resulted in statistically significant (p-value <0.0001) reductions in HbA1c compared to placebo at week 24 (adjusted mean change difference: -0.66% (95% CI: -0.80%, -0.52%).
Gemigliptin: Mechanism of Action: Gemigliptin 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: The benefit of administering gemigliptin in patients with type 2 diabetes and the risk associated with this treatment has been evaluated in the clinical program conducted in total 1473 subjects randomized in 6 clinical trials.
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.
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 for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated that placebo-subtracted mean HbA1c reduction from baseline was -0.705% [95% 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 was evaluated in an active-controlled Phase III study of 24 weeks duration. The analysis of covariance for HbA1c change from baseline at Week 24 (W24 - W0) demonstrated- that the between-group difference (each regimen group of gemigliptin-sitagliptin group) in the least square 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 sulfonylurea therapy: The efficacy and safety of gemigliptin triple combination therapy with metformin and sulfonylurea was evaluated in a placebo-controlled Phase III study of 24 weeks duration. Analysis of covariance (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 least square 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 group was demonstrated.
Gemigliptin and metformin as initial therapy: The efficacy and safety of gemigliptin initial combination therapy with metformin was 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, 95% CI for between group difference in least square 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 CI were less than zero (p <0.001), confirming superiority of the combination therapy group.
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 was evaluated in a multicenter, randomized, active-controlled, parallel group, open-label, exploratory study. The change in MAGE at Week 12 was -43.11mg/dL, -38.27mg/dL and -21.74mg/dL in the gemigliptin and metformin group, sitagliptin and metformin group and glimepiride and metformin group, respectively. In the test result 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).
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.
Dapagliflozin: Mechanism of action: Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2. Dapagliflozin blocks reabsorption of filtered glucose from the S1 segment of the renal tubule, effectively lowering blood glucose in a glucose dependent and insulin-independent manner. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. The increased urinary glucose excretion with SGLT2 inhibition produces an osmotic diuresis, and can result in a reduction in systolic blood pressure.
Pharmacodynamic effects: Dapagliflozin's glucuretic effect is observed after the first dose, is continuous over the 24-hour dosing interval, and is sustained for the duration of treatment. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2 diabetes mellitus following the administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day (corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 diabetes mellitus for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 diabetes mellitus given dapagliflozin 10 mg/day for up to 2 years. Urinary uric acid excretion was also increased transiently (for 3-7 days) and accompanied by a sustained reduction in serum uric acid concentration. At 24 weeks, reductions in serum uric acid concentrations ranged from -48.3 to -18.3 micromoles/L (-0.87 to -0.33 mg/dL).
Clinical efficacy and safety: Dapagliflozin Effect on Cardiovascular Events (DECLARE): Dapagliflozin Effect on Cardiovascular Events (DECLARE) was an international, multicentre, randomised, double-blind, placebo-controlled clinical study conducted to determine the effect of dapagliflozin compared with placebo on cardiovascular outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either at least two additional cardiovascular risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidaemia, hypertension or current tobacco use) or established cardiovascular disease.
Of 17,160 randomised patients, 6,974 (40.6%) had established cardiovascular disease and 10,186 (59.4%) did not have established cardiovascular disease. 8,582 patients were randomised to dapagliflozin 10 mg and 8,578 to placebo, and were followed for a median of 4.2 years.
The mean age of the study population was 63.9 years, 37.4% were female. In total, 22.4% had had diabetes for ≤5 years, mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m².
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m², 7.4% of patients had eGFR <60 mL/min/1.73 m², and 30.3% of patients had micro- or macroalbuminuria (urine albumin to creatinine ratio [UACR] ≥30 to ≤300 mg/g or >300 mg/g, respectively).
Most patients (98%) used one or more diabetic medications at baseline, including metformin (82%), insulin (41%) and sulfonylurea (43%).
The primary endpoints were time to first event of the composite of cardiovascular death, myocardial infarction or ischaemic stroke (MACE) and time to first event of the composite of hospitalisation for heart failure or cardiovascular death. The secondary endpoints were a renal composite endpoint and all-cause mortality.
Pharmacokinetics: Gemigliptin/Dapagliflozin: A bioequivalence study in healthy subjects demonstrated that the Gemigliptin/Dapagliflozin combination tablets are bioequivalent to co-administration of gemigliptin and dapagliflozin as individual tablets.
The effects of food on pharmacokinetics of Gemigliptin/Dapagliflozin combination tablets were similar to the known food effects of gemigliptin or dapagliflozin as individual tablets.
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 clinical 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. When co-administration of a high-fat meal with gemigliptin, food slightly delayed the absorption of gemigliptin, decreased the C_max by 39% but did not affect the AUC. These changes were not considered to be clinically meaningful.
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 of CYP1A2, 2C8, 2C9, 2C19, or 3A4.
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.
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.
Dapagliflozin: Absorption: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (C_max) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin C_max and AUC_τ values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 liters.
Biotransformation: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.
Elimination: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.
Linearity: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.
Renal impairment: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known.
Hepatic impairment: In subjects with mild or moderate hepatic impairment (Child-Pugh class A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean C_max and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.
Elderly: There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients >70 years old.
Gender: The mean dapagliflozin AUC_ss in females was estimated to be about 22% higher than in males.
Race: There were no clinically relevant differences in systemic exposures between White, Black or Asian races.
Body weight: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high-weight somewhat decreased exposure. However, the differences in exposure were not considered clinically meaningful.
Toxicology: Preclinical safety data: No animal studies have been conducted with Gemigliptin/Dapagliflozin.
The following data are findings in studies performed with gemigliptin or dapagliflozin 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 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.
In animal studies, gemigliptin was excreted at a ratio of 1: 4~10 in plasma and milk in rats. Therefore, Gemigliptin/Dapagliflozin should not be administered in nursing woman.
Dapagliflozin: Preclinical studies of dapagliflozin revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, or carcinogenicity.