Pharmacotherapeutic group: Amara-4: Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea derivatives.
Pharmacology: Pharmacodynamics: Amara: Mode of Action: Both in healthy persons and in patients with type 2 diabetes mellitus, Glimepiride decreases blood glucose concentrations, mainly by stimulating insulin release from pancreatic beta cells. This effect is based predominantly on an improved responsiveness of the pancreatic beta cells to the physiological glucose stimulus. While achieving an equivalent reduction in blood glucose, the administration of low doses of Glimepiride to animals and healthy volunteers causes the release of smaller amounts of insulin compared with Glibenclamide. This fact points to the existence of extrapancreatic (insulin-sensitizing and insulin-mimetic) effects of Glimepiride.
Moreover, compared to other sulfonylureas, Glimepiride has less effect on the cardiovascular system. It reduces platelet aggregation (animal and in vitro data) and leads to a marked reduction in the formation of atherosclerotic plaques (animal data).
Insulin release: Like all sulfonylureas, Glimepiride regulates insulin secretion by interacting with the ATP-sensitive potassium channel in the beta cell membrane. Unlike other sulfonylureas, Glimepiride binds specifically to a 65 kDa protein located in the membrane of the beta cell. This interaction of Glimepiride with its binding protein determines the probability of the ATP-sensitive potassium channel being open or closed.
Glimepiride closes the potassium channel. This induces depolarization of the beta cell and results in opening of voltage-sensitive calcium channels and influx of calcium into the cell. Finally, the rise in intracellular calcium concentration activates the release of insulin through exocytosis.
Glimepiride associates with and dissociates from its binding protein much more rapidly and, hence, frequently than glibenclamide. It is assumed that this characteristic high exchange rate of Glimepiride with the binding protein is responsible for its pronounced glucose sensitizing effect and for protecting the beta cells from desensitization and premature exhaustion.
Insulin-sensitizing effect: Glimepiride augments the normal action of insulin on peripheral glucose uptake (human and animal data).
Insulin-mimetic effects: Glimepiride mimics the action of insulin on peripheral glucose uptake and hepatic glucose output.
Peripheral glucose uptake occurs by transport into the muscle and fat cells. Glimepiride directly increases the number of glucose transport molecules in the plasma membranes of muscle and fat cells. The increased influx of glucose causes an activation of the glycosylphosphatidylinositol-specific phospholipase C. As a result, cellular cAMP levels decrease, causing a reduction in activity of protein kinase A; this in turn results in a stimulation of the metabolism of the glucose.
Glimepiride inhibits hepatic glucose output by increasing the concentration of fructose-2,6 bisphosphate which inhibits gluconeogenesis.
Effects on platelet aggregation and formation of atherosclerotic plaques: Glimepiride reduces platelet aggregation in vitro and in vivo. This effect is probably the result of a selective inhibition of cyclooxygenase, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor.
Glimepiride significantly reduces the formation of atherosclerotic plaques in animals. The underlying mechanism has still to be elucidated.
Cardiovascular effects: Through ATP-sensitive potassium channels (see previously mentioned), sulfonylureas also affect the cardiovascular system. Compared with conventional sulfonylureas, Glimepiride has significantly less effect on the cardiovascular system (animal data). This may be explained by the specific nature of its interaction with the binding protein of the ATP-sensitive potassium channel.
Pharmacodynamic Characteristics: In healthy persons, the minimum effective oral dose is approx. 0.6 mg. The effect of Glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, i.e., reduction of insulin secretion, is still present under Glimepiride.
There was no significant difference in effect regardless of whether the drug was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with one single dose. Moreover, in a clinical study, good metabolic control was even achieved in 12 out of 16 patients with renal insufficiency (creatinine clearance 4 to 79 mL/min).
Although the hydroxy metabolite of Glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect.
Combination therapy with metformin: In patients not adequately controlled with the maximum dosage of either Glimepiride or metformin, combination therapy with both oral antidiabetic agents can be initiated.
The improvement in metabolic control in conjunction with combination treatment as compared to treatment with either medicinal product alone has been verified in two studies.
Combination therapy with insulin: In patients not adequately controlled with the maximum dosage of either Glimepiride or metformin, combination therapy with both oral antidiabetic agents can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.
Clinical Efficacy/Clinical Studies: An active controlled clinical trial (Glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 randomized children (8-17 years of age) with type 2 diabetes. Both Glimepiride and metformin exhibited a significant decrease from baseline in HbA1c.
No significant difference was observed between treatment groups. Glimepiride failed to demonstrate non-inferiority to metformin.
Following Glimepiride treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.
Amara-4: Glimepiride is an orally active hypoglycaemic substance belonging to the sulfonylurea group. It may be used in non-insulin dependent (type 2) diabetes mellitus.
Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells. As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.
Insulin release: Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane. Closing the potassium channel induces depolarisation of the beta cell and results - by opening of calcium channels - in an increased influx of calcium into the cell. This leads to insulin release through exocytosis.
Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfonylureas binding site.
Extrapancreatic activity: The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.
The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins, located in the cell membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.
Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C, which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.
Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6-bisphosphate, which in its turn inhibits the gluconeogenesis.
General: In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under glimepiride.
There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose.
Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect.
Combination therapy with metformin: Improved metabolic control for concomitant glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum daily dosage of metformin has been shown in one study.
Combination therapy with insulin: Data for combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of glimepiride, concomitant insulin therapy can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.
Special populations: Paediatric population: An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2 diabetes.
Both glimepiride and metformin exhibited a significant decrease from baseline in HbA1c (glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, glimepiride did not achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA1c. The difference between treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority margin.
Following glimepiride treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.
Pharmacokinetics: Amara: The primary mechanism of action of Glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as Glimepiride. This supported by both pre-clinical and clinical studies demonstrating that the Glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. This findings are consistent with the results of a long term randomized, placebo-controlled trial in which Glimepiride therapy improved postprandial insulin/C-peptide levels responses and overall glycemic controlled without producing clinically meaningful increased in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which Glimepiride lowers blood glucose during long-term administration has not been clearly established.
Amara-4: Absorption: The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only the absorption rate is slightly diminished. Maximum serum concentrations (Cmax) are reached approx 2.5 hours after oral intake (mean 0.3 μg/mL during multiple dosing of 4 mg/daily) and there is a linear relationship between dose and both Cmax and AUC (area under the time concentration curve).
Distribution: Glimepiride has a very low distribution volume (approx. 8.8 litres), which is roughly equal to the albumin distribution space, high protein binding (>99%) and a low clearance (approx. 48 ml/min).
In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood-brain barrier is low.
Biotransformation and Elimination: Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.
After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites most probably resulting from hepatic metabolism (major enzyme is CYP2C9) were identified both in urine and faeces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3 to 6 and 5 to 6 hours respectively.
Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intra individual variability was very low. There was no relevant accumulation.
Special populations: Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding.
Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed in such patients.
Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.
Paediatric population: A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30 paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed mean AUC(0-last), Cmax and t1/2 similar to that previously observed in adults.
Mechanism of Action: Glimepiride distinctly lowers the blood glucose level by both the defects associated with Type 2 diabetes, by stimulating pancreatic beta cells to produce more insulin, and induce increased activity of peripheral insulin intra cellular receptor.
Clinical Pharmacology: With Glimepiride GI absorption is complete with no interference of meals. Significant absorption of glimepiride is seen within one hour, and distributed throughout the body, bound to the plasma protein to an extent of 99.5% and it is metabolised by oxidative biotransformation and 60% is excreted in the urine, and the remaining is excreted in the faeces.