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- Availability date:2020-07-30
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mechanism of action. dapagliflozin is a high-power (ki: 0.55 nm), selective and reversible inhibitor of the sodium-dependent cotransporter of type 2 glucose (nktc2).
NZKTG2 is selectively expressed in non-expressed kidneys in 70 other tissues, including the liver, skeletal muscle, adipose tissue, mammary gland, bladder and brain. NZKTG2 is the main carrier responsible for the reabsorption of glucose from the glomerular filtrate back into the bloodstream. Despite the presence of hyperglycemia in type II diabetes mellitus, reabsorption of filtered glucose continues. Dapagliflozin improves fasting and post-food plasma glucose levels by reducing renal glucose reabsorption, which leads to urine glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose of the drug, lasts for a 24-hour dosing interval and persists throughout treatment. The amount of glucose secreted by the kidneys using this mechanism depends on the concentration of glucose in the blood and the rate of glomerular filtration (GFR). Dapagliflozin does not affect the normal production of endogenous glucose in response to hypoglycemia. Dapagliflozin acts independently of the secretion and action of insulin. In clinical studies of the Forksig preparation, an improvement in the function of beta cells (HOMA beta cells) is observed in evaluating the homeostasis model.
Urinary glucose excretion (glucuresis), induced by dapagliflozin, is associated with calorie loss and weight loss. Inhibition of co-transport of glucose and sodium by dapagliflozin is also associated with minor diuresis and temporary excretion of sodium in the urine. Dapagliflozin does not inhibit other glucose transporters (which is important for transporting glucose to peripheral tissues) and is 1400 times more selective for NZKTG2 compared to NZKTG1, the main intestinal transporter responsible for glucose absorption.
Pharmacodynamic effects. In healthy study participants and patients with type II diabetes mellitus, after the use of dapagliflozin, an increase in the amount of glucose excreted in the urine was observed. About 70 g of glucose per day was excreted in the urine (which corresponds to 280 kcal / day) with dapagliflozin at a dose of 10 mg / day for patients with type II diabetes mellitus for 12 weeks. Patients with type II diabetes mellitus who received dapagliflosin at a dose of 10 mg / day for a period of up to 2 years showed signs of prolonged glucose excretion.
Such urinary glucose excretion when using dapagliflozin also leads to osmotic diuresis and an increase in urine volume in patients with type II diabetes mellitus. An increase in urine volume in patients with type II diabetes mellitus reaches ≈375 ml / day. An increase in urine volume was associated with a slight and temporary increase in urinary sodium excretion, which was not accompanied by changes in serum sodium concentration.
Urinary urinary acid excretion was also temporarily increased (within 3–7 days) and was accompanied by a steady decrease in the concentration of uric acid in the blood plasma. At the 24th week, a decrease in the concentration of uric acid in blood serum varied from –48.3 to –18.3 mcmol / L (from –0.87 to –0.33 mg / dl).
Clinical efficacy and safety. 14 double-blind, randomized, controlled clinical trials were conducted in 7056 patients with type II diabetes mellitus in order to evaluate the efficacy and safety of the Forksig preparation; 4,737 patients in these studies received dapagliflozin treatment. In 12 studies, the treatment period was 24 weeks, in 8 long-term follow-ups from 24 to 80 weeks (up to a total study duration of 104 weeks) in one study, the treatment period was 28 weeks, and in another study, the treatment duration was 52 weeks with long-term continuation 52 and 104 weeks (total study duration 208 weeks).The average disease duration for participants with diabetes was 1.4–16.9 years. 50% of patients noted mild renal impairment, and 11% - moderate renal impairment. 51% of the participants were men, 84% belonged to the Caucasian race, 8% to the Mongoloid, 4% to the Negroid and 4% to other ethnic groups. In 81% of participants, body mass index (BMI) was ≥27. In addition, two 12-week placebo-controlled studies were conducted with patients with inadequate control of type II diabetes and hypertension.
Monotherapy. A double-blind, placebo-controlled study lasting 24 weeks (with an additional continuation period) was conducted to assess the safety and effectiveness of Forksig monotherapy in patients with inadequate control of type II diabetes mellitus. Taking dapagliflozin once a day caused a statistically significant (p0.0001) decrease in the level of HbA1c compared with placebo (see table 1).
During the continuation period, the decrease in the HbA1c level continued until the 102nd week inclusive (the average change from the initial level with a correction of –0.61 and –0.17% for dapagliflozin 10 mg and placebo, respectively).
Table 1. Results after 24 weeks (PVDOSand) a placebo-controlled study of the use of dapagliflozin as monotherapy
|Change from baseline at||–0,89||–0,23|
|Difference compared to placeboat (95% CI)||–0,66*
|Patients (%) who achieved HbA1c of 7%
Adjusted for baseline
|Change from baseline at||–3,16||–2,19|
|Difference compared to placebo at (95% CI)||–0,97
andPVDOS - transfer of data from the last observation (before treatment of treated patients).
bAll randomized patients who received at least 1 dose of the drug tested in the short-term double-blind study period.
atLeast squares average adjusted to the initial value.
* P-value of 0.0001 compared with placebo.
§Not evaluated by statistical significance as a result of a sequential testing procedure for secondary endpoints.
Additional combination therapy. In a 52-week active-controlled study, to obtain evidence of no less efficacy of the study drug (with periods of 52 and 104 weeks), the effect of the Forksig drug was evaluated when added to metformin compared with sulfonylurea (glipizide), when added to metformin in patients with insufficient glycemic control (HbA1c 6.5% and ≤10%). The results indicated a similar average decrease in HbA1c from baseline after 52 weeks compared with glipizide, which demonstrated no less efficacy of the study drug. After 104 weeks, the adjusted mean change in HbA1c from baseline was –0.32% for dapagliflozin and –0.14% for glipizide. After 208 weeks, the adjusted mean change in HbA1c from baseline was –0.10% for dapagliflozin and 0.20% for glipizide. After 52, 104 and 208 weeks, a significantly smaller proportion of patients in the dapagliflozin treatment group (3.5; 4.3 and 5.0%, respectively) had at least one episode of hypoglycemia compared with the group receiving glipizide (40.8; 47.0 and 50.0% respectively). The proportion of patients who continued to participate in the study at the time of 104 and 208 weeks was 56.2 and 39.7% for the dapagliflozin treatment group and 50.0 and 34.6% for the glipizide treatment group.
Dapagliflozin as an adjunct to metformin, glimepiride, metformin and sulfonylurea, sitagliptin (with or without metformin) or insulin caused a statistically significant decrease in HbA1c after 24 weeks compared with placebo (p0,0001).
The decrease in HbA1c, which was observed at 24 weeks, continued in studies of additional combination therapy (glimepiride and insulin) up to 48 weeks (glimepiride) and up to 104 weeks (insulin).After 48 weeks, when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for dapagliflozin at a dose of 10 mg and placebo was –0.30 and 0.38%, respectively. In the study with the addition of metformin, the decrease in HbA1c persisted after 102 weeks (the adjusted average change from the baseline was –0.78 and 0.02% for the drug at a dose of 10 mg and placebo, respectively). After 104 weeks when using insulin (with or without additional oral hypoglycemic drugs), the adjusted average change from the initial level of HbA1c reduction was ndas
Tags: Forxiga® [Dapagliflozin]