Galvus Met Mechanism of Action

ATC code: A10BD08.
Pharmacology: Pharmacodynamics: Mechanism of action: Galvus Met: Galvus Met combines two antihyperglycaemic agents with different mechanisms of action to improve glycaemic control in patients with type 2 diabetes: Vildagliptin is a DPP-4 (dipeptidyl-peptidase-4) inhibitor, and metformin is a member of the biguanide class.
Vildagliptin: Administration of vildagliptin inhibits DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with 50 to 100 mg vildagliptin daily in patients with type 2 diabetes significantly improved markers of beta cell function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently employed meal tolerance test. In non-diabetic (normoglycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.
The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.
The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment.
Metformin: Mechanism of action: Metformin is an oral antidiabetic agent of the biguanide class, whose hypoglycaemic effect is based primarily on the overcoming of insulin resistance in liver and muscle. In the presence of insulin, it lowers both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion and, when used alone, does not produce hypoglycaemia.
The hypoglycaemic effect is based on three mechanisms: In the liver: Hepatic glucose production is largely responsible for hyperglycaemia in the fasting state. Metformin reduces hepatic glucose production activated by insulin resistance by inhibiting gluconeogenesis and glycogenolysis, thereby at the same time counteracting the hyperglycaemic effect of glucagon. By this mechanism, metformin reduces fasting hyperglycaemia.
In muscle: Impaired peripheral glucose uptake and storage are mainly responsible for postprandial hyperglycaemia. Metformin increases cellular sensitivity to insulin by stimulating insulin-receptor tyrosine kinase activity, thereby promoting cellular glucose uptake. Metformin increases the capacity of all cell-membrane glucose transporters (GLUTs). This effect of metformin is particularly marked in hyperglycaemic states. Intracellular glycogen synthesis is increased by stimulation of the key enzyme, glycogen synthase. By this mechanism, metformin reduces postprandial hyperglycaemia.
In the intestine: Metformin delays intestinal glucose absorption, thereby reducing postprandial glucose exposure.
Effects on lipid metabolism and fibrinolysis: Metformin also has a positive effect on human lipid metabolism, independently of its effect on blood glucose. Medium- and long-term controlled clinical studies have demonstrated that therapeutic doses of metformin reduce total cholesterol, LDL cholesterol and triglyceride levels. In addition, metformin was shown in some studies to increase HDL cholesterol levels.
Metformin also possesses fibrinolytic properties.
Clinical efficacy: Galvus Met: There have been no studies of the clinical efficacy of Galvus Met. The safety and efficacy of the separate components have already been established. Co-administration of the two components has been evaluated for safety and efficacy in two clinical studies. Both of these studies demonstrated an added benefit for vildagliptin in patients with inadequately controlled type 2 diabetes who had been treated with metformin.
In a 24-week, double-blind, placebo-controlled study in patients with type 2 diabetes whose glycaemia was inadequately controlled on metformin alone at doses ≥2000 mg, vildagliptin combined with metformin showed a statistically significantly greater reduction in HbA_1c than that achieved in the group using metformin and placebo (the mean difference was -0.7% in the group using 50 mg vildagliptin once daily and -1.1% in the group using 50 mg vildagliptin twice daily).
The efficacy of vildagliptin in combination with 1000 mg metformin was evaluated in another double-blind, placebo-controlled clinical study of 52 weeks' total duration (12-week core study [n = 132] plus a 40-week extension [n = 71]). The addition of vildagliptin (50 mg once daily) to metformin resulted in an additional and statistically significant reduction in mean HbA_1c from baseline (0.55%), compared with the group using metformin plus placebo (+0.1%), at the end of the first 12 weeks of the study (mean baseline HbA_1c of 7.7% and 7.9%, respectively). At 52 weeks, the mean change from baseline HbA_1c was statistically significantly greater and more marked in the group using vildagliptin (50 mg) plus metformin than in the group on metformin alone (between-group difference of -1.1%).
In a 24-week trial in patients whose blood glucose was inadequately controlled with metformin, 50 mg vildagliptin twice daily was compared with 30 mg pioglitazone once daily. Mean reductions from baseline HbA_1c (8.4%) were 0.9% with vildagliptin added to metformin and 1.0% with pioglitazone added to metformin. For baseline HbA_1c >9.0%, the decrease was greater (1.5%) in both treatment groups. Patients receiving pioglitazone in addition to metformin experienced an increase in weight of 1.9 kg. Those receiving vildagliptin in addition to metformin gained 0.3 kg in weight. In a long-term trial lasting up to two years, 50 mg vildagliptin twice daily was compared with up to 6 mg glimepiride once daily in patients treated with metformin. After two years, mean reductions in HbA_1c were 0.06% with the vildagliptin/metformin combination and 0.14% with glimepiride/metformin. The change in body weight was -0.2 kg with vildagliptin and +1.2 kg with glimepiride. The incidence of hypoglycaemic episodes was significantly lower in the vildagliptin group (2.3%) than in the glimepiride group (18.2%).
In a 52-week study in patients whose blood glucose was inadequately controlled with metformin, twice-daily 50 mg doses of vildagliptin added to metformin were compared with gliclazide at a dose of up to 320 mg daily added to metformin. After 1 year, mean reductions in HbA_1c were 0.81% with the combination of vildagliptin/metformin (baseline HbA_1c 8.4%) and 0.85% with gliclazide/metformin (baseline HbA_1c 8.5%); statistical non-inferiority was demonstrated. Patients receiving gliclazide in addition to metformin gained 1.4 kg, while those receiving vildagliptin in addition to metformin gained 0.1 kg. Five patients (1.0%) in each group had at least one hypoglycaemic episode.
A 24-week trial evaluated the efficacy of the fixed-dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in drug-naïve patients. Mean baseline HbA_1c (8.6%) decreased by 1.82% on vildagliptin/metformin 50 mg/1000 mg twice daily, by 1.61% on vildagliptin/metformin 50 mg/500 mg twice daily, by 1.36% on metformin 1000 mg twice daily and by 1.09% on vildagliptin 50 mg twice daily. The decrease in HbA_1c was greater in patients with a mean baseline ≥10.0%.
A 24-week randomized, double-blind, placebo-controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 U) with or without metformin. Vildagliptin in combination with insulin significantly decreased HbA_1c compared with placebo: In the overall population, the placebo-adjusted reduction from a mean baseline HbA_1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in HbA_1c was -0.63% and -0.84%, respectively. Hypoglycaemia occurred in 8.4% and 7.2% of patients treated with vildagliptin and placebo, respectively. The patients' mean weight showed little overall change (+0.2 kg on vildagliptin and -0.7 kg on placebo).
A 24-week randomized, double-blind, placebo-controlled trial was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA_1c compared with placebo: the placebo-adjusted mean reduction from a mean baseline HbA_1c of 8.8% was -0.76%.
Vildagliptin: Two 24-week, double-blind, placebo-controlled trials were carried out in treatment-naïve patients with type 2 diabetes. In these studies, administration of 50 mg vildagliptin once daily resulted in mean changes from baseline in HbA_1c ( -0.8% and -0.5%) that were statistically significant compared with placebo.
In addition, vildagliptin monotherapy was compared to metformin, rosiglitazone or pioglitazone in several studies in treatment-naïve patients. The patients had had diabetes for an average of two years. In these studies, vildagliptin showed a clinically relevant reduction in HbA_1c as compared with baseline. Non-inferiority was statistically demonstrated as compared with rosiglitazone, but not as compared with metformin and pioglitazone.
In a two-year long-term trial, 50 mg vildagliptin twice daily was compared with daily doses of up to 320 mg gliclazide. After two years, mean reductions in HbA_1c were 0.5% with vildagliptin and 0.6% with gliclazide. There was less weight gain with vildagliptin (0.75 kg) and fewer hypoglycaemic episodes (0.7%) than with gliclazide (1.6 kg and 1.7%, respectively).
The studies of combinations with metformin are described above.
A 52-week multi-center, randomized, double-blind trial was conducted in patients with type 2 diabetes and congestive heart failure (NYHA class I - III) to evaluate the effect of vildagliptin 50 mg bid (N=128) compared to placebo (N=126) on left ventricular ejection function (LVEF). Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing CHF. Adjudicated cardiovascular events were overall balanced. There were slightly more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However there were imbalances in baseline CV risk favoring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA_1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8%. The incidence of hypoglycemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.
Cardiovascular risk: A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV monotherapy and combination therapy clinical studies of up to more than 2 years in duration was performed. It involved 9,599 patients with type 2 diabetes treated with vildagliptin 50 mg qd or 50 mg bid and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk. The composite endpoint of adjudicated major adverse cardio-vascular events (MACE) including acute myocardial infarction, stroke or CV death was similar for vildagliptin versus combined active and placebo comparators [Mantel-Haenszel risk ratio 0.82 (95% confidence interval 0.61-1.11)] supporting the cardiovascular safety of vildagliptin. A MACE occurred in 83 out of 9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator treated patients. Assessment of each individual MACE components showed no increased risk (similar M-H RR). Confirmed HF events defined as HF requiring hospitalization or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with M-H RR 1.08 (95% CI 0.68-1.70) showing no increased risk of HF in vildagliptin treated patients.
Metformin: The prospective, randomized UKPDS study (UK Prospective Diabetes Study) has established the long-term benefit of intensive glycaemic control in patients with type 2 diabetes. Analysis of the results for overweight patients - treated with metformin after failure of diet alone - showed: a significant reduction in the absolute risk of diabetes-related complications in the metformin group (29.8 events/1000 patient-years) vs. both diet alone (43.3 events/1000 patient-years), p = 0.0023, and the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034; a significant reduction in the absolute risk of diabetes-related mortality: 7.5 events/1000 patient-years with metformin, 12.7 events/1000 patient-years on diet alone (p = 0.017); a significant reduction in the absolute risk of overall mortality: 13.5 events/1000 patient-years with metformin vs. 20.6 events/1000 patient-years on diet alone (p = 0.011) and 18.9 events/1000 patient-years for the combined sulphonylurea and insulin monotherapy groups (p = 0.021); a significant reduction in the absolute risk of myocardial infarction: 11 events/1000 patient-years with metformin vs. 18 events/1000 patient-years on diet alone (p = 0.01).
Pharmacokinetics: Absorption: Galvus Met: In bioequivalence studies of Galvus Met at three dosage strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) vs. free combination of vildagliptin and metformin at the corresponding doses, the bioavailability of both vildagliptin and metformin were shown to be unchanged.
Food does not affect the extent or rate of absorption of vildagliptin. The C_max and AUC of metformin decreased by 26% and 7%, respectively, when given with food, and the absorption of metformin was delayed (T_max: 2.0 to 4.0 hours). These changes in C_max and AUC are consistent, but lower than those observed when metformin alone was given with food. The effects of food on the pharmacokinetics of both the vildagliptin and metformin components of Galvus Met were similar to those when vildagliptin and metformin alone were given with food.
Vildagliptin: Vildagliptin is rapidly absorbed with an oral bioavailability of 85%. Peak plasma concentrations are attained after about 1 hour. Ingestion of food has no relevant effect on absorption. Food does not alter overall exposure (AUC).
Metformin: Following oral administration, T_max is 2.5 hours, and absorption is complete after 6 hours. Absorption is assumed to take place primarily in the upper gastrointestinal tract. The absolute bioavailability of a 500 mg or 850 mg dose is approximately 50-60% in healthy subjects. Ingestion of a single oral dose of 500-2500 mg was followed by a less than proportional increase in C_max, possibly due to a saturable mechanism. Using standard metformin dosages, steady-state plasma levels are reached within 24-48 hours. These are generally lower than 1 µg/ml. In controlled clinical studies, C_max was not found to exceed 4 µg/ml, even at maximum doses.
Food decreases and delays the absorption of metformin. Following ingestion of an 850 mg dose with food, a 40% lower C_max, 25% decrease in AUC and 35-minute prolongation of T_max were observed. The clinical relevance of these findings is thus far unknown.
Distribution: Vildagliptin: The plasma protein binding of vildagliptin is low (9.3%), and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady state after intravenous administration (V_ss) is 71 litres.
Metformin: Plasma protein binding of metformin is negligible. Metformin diffuses to some extent into erythrocytes. Peak blood levels are lower than the peak plasma levels and are achieved at approximately the same time. The red blood cells probably represent a secondary compartment of distribution.
The mean volume of distribution is 63-276 litres.
It is not known whether metformin crosses the placenta or is excreted in breast milk. In rats, small amounts pass into the milk.
Metabolism: Vildagliptin: Vildagliptin is largely metabolized (69% of the dose), partly by DPP-4. The major metabolite, LAY151 (57% of the dose), which is formed by hydrolysis, is inactive. There is also an amide hydrolysis product (4% of the dose). Vildagliptin is not metabolized by cytochrome P450 enzymes.
Metformin: Metformin is not metabolized in humans.
Elimination: Vildagliptin: 85% of the dose is excreted in the urine and 15% of the dose is recovered in the faeces. Unchanged vildagliptin accounts for 23% of the dose. The elimination half-life is approximately 3 hours.
Metformin: Metformin is excreted unchanged in the urine. Renal clearance is >400 ml/minute, and hence some 3.5 times greater than creatinine clearance. The drug is thus chiefly eliminated by active tubular secretion. The plasma elimination half-life after oral dosing is about 6.5 hours. When measured in whole blood, the half-life is approximately 17.6 hours.
In subjects with normal renal function, metformin does not accumulate in the body at the standard dosage (1500-2000 mg).
Pharmacokinetics in special patient populations: Sex: Vildagliptin: No differences in the pharmacokinetics of vildagliptin have been observed between men and women.
Elderly patients: Vildagliptin: Plasma concentrations are elevated in patients over 70 years of age. However, the change in exposure to vildagliptin is not clinically relevant.
Hepatic impairment: Vildagliptin: Exposure to vildagliptin (100 mg) was not elevated after a single dose of 100 mg in patients with mild and moderate hepatic impairment. In patients with severe hepatic impairment, exposure was increased by 22% (68% upper CI limit).
Renal impairment: Vildagliptin: Systemic exposure to vildagliptin was elevated in patients with mild, moderate or severe renal impairment and in ESRD patients on haemodialysis; it was elevated by 58% in patients with severe renal impairment (102% upper CI limit).
Metformin: In patients with renal impairment, renal clearance decreases in proportion to creatinine clearance, with the elimination half-life prolonged and a risk of accumulation.
Toxicology: Preclinical data: Animal studies of up to 13 weeks have been conducted with the combined active substances of Galvus Met. No new toxicities associated with the combination were identified. The following data are findings from studies performed with vildagliptin or metformin individually.
Vildagliptin: In a distribution study in rats, concentrations measured in kidney and liver tissue were 10-30 times higher than concentrations in the plasma.
At in vitro concentrations and dog in vivo plasma concentrations that markedly exceeded C_max-based exposure levels in humans given 50 mg vildagliptin (80-260 times higher for the in vitro findings and 43 times higher for the in vivo findings), an inhibitory action on cardiac sodium channels, a decreased rate of depolarization in Purkinje fibres, slowed conduction in isolated rabbit hearts and a widening of the QRS complex in the ECG of dogs were observed.
A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 370 times human AUC exposure at 50 mg). No increases in tumour incidence attributable to vildagliptin were observed. A two-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg (up to 420 times human AUC exposure at the 50 mg dose). The incidence of mammary tumours was increased in female mice at a dose approximately 260 times higher than the human dose of 50 mg vildagliptin; mammary tumours were not more frequent at approximately 100 times the human exposure. The incidence of haemangiosarcoma was increased in male mice at AUC exposure levels ≥74 times the human dose of 50 mg vildagliptin, and in female mice at around 260 times the human exposure. No significant increase in the incidence of haemangiosarcoma was observed in males at approximately 27 times the human exposure to vildagliptin, and in females at approximately 100 times the human exposure.
Vildagliptin was not mutagenic in a variety of mutagenicity tests including a bacterial reverse mutation Ames assay and a human lymphocyte chromosomal aberration assay. Oral bone marrow micronucleus tests in both rats and mice did not reveal clastogenic or aneugenic potential at up to 2000 mg/kg, or approximately 2000 times the human dose. An in vivo mouse liver comet assay using the same dose was also negative.
In a 13-week toxicity study in cynomolgus monkeys, skin lesions were recorded at doses ≥5 mg/kg/day. These lesions were confined to the extremities (hands, feet, ears and tail).
At 5 mg/kg/day (AUC-based exposure slightly higher than human exposure at the 50 mg dose), only blisters were observed. These were reversible despite continued treatment, and were not associated with histopathological abnormalities.
Flaking skin, peeling skin, scabs and tail sores in connection with histopathological changes were noted at doses above 20 mg/kg/day (approximately 5 times human AUC exposure at the 50 mg dose).
Necrotic lesions of the tail were observed at ≥80 mg/kg/day.
Skin lesions were reversible (up to at least 80 mg/kg) if administration was stopped before necrosis occurred.
Skin lesions have not been observed in humans or in other species given vildagliptin.
Metformin: Preclinical study data have yielded no evidence of special risks for human use, based on studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity.
Reproductive toxicity: Metformin has no effect on fertility, is not teratogenic and does not influence neonatal development.
Mutagenicity: All study results (Ames test, gene mutation test, chromosome aberration test, micronucleus test) have shown that metformin has no mutagenic or clastogenic effects.
Carcinogenicity: Metformin is not carcinogenic in rodents given doses of up to 900 mg/kg/day (rats) and 1500 mg/kg/day (mice).