Glimepiride

Glimepiride is an Anti-diabetic Agent belonging to the pharmacology class of second-generation sulfonylureas.

Glimepiride is approved for treating type 2 diabetes mellitus in adults. It helps reduce blood sugar levels by stimulating the pancreas to release more insulin.

Glimepiride is taken orally and is well absorbed by the gastrointestinal tract. It circulates throughout the body, mainly interacting with plasma proteins. Metabolism happens in the liver, where inactive metabolites are formed. These metabolites are primarily eliminated through renal excretion.

The most common side effects of glimepiride include low blood sugar levels (hypoglycemia), nausea, headache, weakness, and dizziness.

Glimepiride is available in the form of oral Tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Brazil, South Africa, Germany and Australia.

Glimepiride is an Anti-diabetic Agent belonging to the pharmacology class of second-generation sulfonylureas.

Intracellular ATP and ADP activate pancreatic beta cell ATP-sensitive potassium channels. The channel's hetero-octomeric complex comprises four pore-forming Kir6. 2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing enables the creation of channels of distinct subunit isoforms expressed at various amounts in different organs. ATP-sensitive potassium channels are critical metabolic sensors and regulators in pancreatic beta cells, coupling membrane excitability with glucose-stimulated insulin secretion (GSIS). When the ATP: ADP ratio decreases, the channels are activated and open, resulting in K+ outflow from the cell, membrane hyperpolarization, and inhibition of insulin secretion. On the other hand, increased glucose uptake into the cell causes an increase in the intracellular ATP: ADP ratio, which causes channel closure and membrane depolarization. Depolarization causes activation and opening of voltage-dependent Ca2+ channels, resulting in an influx of the calcium ions into the cell. Increased intracellular calcium levels induce the actomyosin filaments responsible for the exocytosis of insulin granules contained in vesicles to contract. Glimepiride inhibits the ATP-sensitive potassium channel by binding non-specifically to the B sites of the sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits, as well as the A site of SUR1 subunit of channel to boost insulin secretion from the beta cell.

Glimepiride is available in oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Glimepiride treats type 2 diabetes, characterized by high blood sugar levels. When used in combination with a healthy diet and exercise, this helps people with type 2 diabetes reduce their blood sugar levels and can improve glycemic control. Usually, glimepiride is recommended when dietary modifications alone are insufficient to control diabetes.

In Treatment of Type 2 diabetes mellitus

Glimepiride helps increase the amount of insulin your body produces (in the pancreas). It works by boosting the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of developing any significant consequences of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

Glimepiride is indicated as a monotherapy for treating type 2 diabetes in the adults as an adjunct to diet and exercise to enhance glycemic control.

It may also be used with metformin or insulin to reduce blood glucose in type 2 diabetes patients whose high blood sugar levels cannot be controlled by diet and exercise alone, in addition to oral hypoglycemic (a medicine used to lower blood sugar levels).

Use Limitations

Glimepiride tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis because they are ineffective.

Orally: Glimepiride is available as a tablet that can be taken orally. Glimepiride should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 0.5 mg, 1mg, 2mg, 3 mg or 4 mg

Glimepiride is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

Type 2 Diabetes Mellitus

Initial dose: 1-2 mg PO qAM after breakfast or with a first meal; dose may be increased by 1-2 mg every 1-2 weeks; maximum daily dose: 8 mg

Other oral hypoglycemic agents conversion

Because of the possibility of overlapping hypoglycemia effects, patients should be closely monitored for 1-2 weeks after switching from extended half-life sulfonylureas to glimepiride.

Dosing Considerations

If the glycemic response to glimepiride is insufficient at the maximal dose, combine it with insulin or metformin.

Glimepiride should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

Taking glimepiride before or with meals is advised, as it enhances insulin release when glucose levels rise after eating.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation, causing hypoglycemia (low blood sugar).

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Glimepiride may be contraindicated in the following conditions:-

• Known hypersensitivity to glimepiride or any of the product's ingredients.
• Hypersensitivity to sulfonamide derivatives.
• Type 1 diabetes
• Diabetic ketoacidosis with or without coma

• Hypoglycemia: This condition can be severe. Ensure correct patient selection, dose, and instructions, especially in high-risk populations (e.g., the elderly and renal-impaired patients) and when combined with other anti-diabetic drugs.
• Hypersensitivity Postmarketing reports of allergy, angioedema, and Stevens-Johnson Syndrome have been received. Discontinue glimepiride immediately, check for other causes, institute appropriate monitoring and therapy, and begin alternative diabetic management.
• Hemolytic anaemia can arise when the enzyme glucose 6-phosphate dehydrogenase (G6PD) is insufficient. Consider a non-sulfonylurea substitute.
• Sulfonylureas May Increase the Risk of Cardiovascular Death: Inform the patient with the dangers, benefits, and treatment options.
• Macrovascular Results: No definitive clinical studies have demonstrated that glimepiride or any other anti-diabetic treatment reduces macrovascular risk.

It is unsafe to consume glimepiride with alcohol.

There is no sufficient scientific evidence regarding the use and safety of glimepiride in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.

Increase intake of fibre-rich foods and minimize the carbohydrate or sugary intake.

The adverse reactions related to glimepiride can be categorized as

• Common Adverse Effects: Hypoglycemia.
• Less Common Adverse Effects: Dizziness, asthenia, headache, nausea
• Rare Adverse Effects: Liver function abnormalities, blood disorders, allergic reactions (e.g., skin itching, hives) or photosensitivity (sensitivity to sunlight)

Reports on Postmarketing

Severe hypersensitivity reactions, such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome.

Anaemia of hemolysis in patients with and without G6PD deficiency

Hepatic impairment (e.g., cholestasis, jaundice) and hepatitis, which can develop into liver failure, are all possibilities.

Porphyria cutanea tarda, photosensitivity responses, and allergic vasculitis are among the conditions that can occur.

Aplastic anaemia, leukopenia, agranulocytosis, and pancytopenia

Thrombocytopenia (including severe cases with platelet counts of 10,000/mcL) and thrombocytopenic purpura can also occur.

Disulfiram-like responses and hepatic porphyria reactions

Hyponatremia and SIADH are common in people taking other drugs or have medical disorders that produce hyponatremia or enhance antidiuretic hormone secretion.

Dysgeusia

Alopecia

The clinically relevant drug interactions of glimepiride are briefly summarized here:

• Certain drugs can interfere with glucose metabolism, necessitating Glimepiride dose adjustments and strict monitoring of blood glucose levels.
• Miconazole: When used with glimepiride, severe hypoglycemia may occur. Miconazole is used concurrently.
• Cytochrome P450 2C9 interactions: Cytochrome P450 2C9 inhibitors and inducers may affect glycemic control by affecting glimepiride plasma concentrations.
• Colesevelam: Coadministration with glimepiride may impair absorption. Glimepiride should be taken at least 4 hours before colesevelam.

• Pregnancy

Pregnancy Category C: Use with caution if the benefits outweigh the risks.

There are no adequate and well-controlled studies of glimepiride in pregnant population .

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Diabetes poorly treated during pregnancy raises the risk of diabetic ketoacidosis, preeclampsia, spontaneous abortions, premature birth, and delivery difficulties. Diabetes that is not well controlled increases the prenatal risk of severe birth abnormalities, stillbirth, and macrosomia-related morbidity.

Adverse Fetal/Neonatal Reactions

Women with gestational diabetes who use sulfonylureas throughout pregnancy may have an increased risk of neonatal intensive care hospitalization, respiratory distress, hypoglycemia, birth damage, and being large for gestational age. Prolonged severe hypoglycemia lasting over 4 to 10 days has been documented in neonates born to mothers who received a sulfonylurea at the time of delivery, as has the use of drugs having a long half-life. Monitor neonates for hypoglycemia and respiratory distress and manage as required.

Dose adjustments during pregnancy and postpartum period

Because of cases of severe hypoglycemia in neonates born to mothers taking a sulfonylurea at birth, glimepiride should be stopped at least two weeks before planned delivery.

Animal Data

There were no effects on embryo-fetal development in animal studies after administering glimepiride to pregnant rats and rabbits at oral doses approximately 4000 times and 60 times the maximum human quantity based on the body surface area, respectively; however, fetotoxicity was observed in rats and rabbits at doses 50 times and 0.1 times the maximum human amount, respectively.

• Nursing Mothers

Breastfed infants of breastfeeding mothers on glimepiride should be assessed for hypoglycemic symptoms. Glimepiride is not known to be excreted in human milk, and there is no data on its effects on milk production. Glimepiride can be found in rat milk. The developmental and health benefits of breastfeeding should be addressed with the mother's clinical requirement for glimepiride and any potential detrimental effects of glimepiride or the underlying maternal disease on the breastfed child.

Clinical Considerations

Monitoring for adverse reactions

Monitor for indications of hypoglycemia in breastfed newborns (e.g., jitters, cyanosis, apnea, hypothermia, extreme drowsiness, poor feeding, seizures).

Data

In rats, significant quantities of glimepiride were found in breast milk and pup serum during prenatal and postnatal experiments. During the postnatal period, offspring of rats exposed to high amounts of glimepiride during pregnancy and lactation showed skeletal abnormalities consisting of humeral shortening, thickening, and bending. These skeletal deformations were determined to be the outcome of glimepiride-exposed mothers' nursing.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

• Geriatric Use

In glimepiride clinical trials, 1053 of 3491 patients (30%) were above the age of 65. There were no overall variations in safety or effectiveness between these patients and younger ones. However, certain elderly patients may be more sensitive. Glimepiride pharmacokinetics did not differ significantly between patients with type 2 diabetes aged 65 years (n=49) and those aged >65 years (n=42).

The kidney excretes a significant amount of glimepiride. Renal dysfunction is more common in elderly persons. Furthermore, hypoglycemia in the elderly may be difficult to detect. In this patient population, use caution when starting glimepiride and increasing the dose of glimepiride.

Dosage adjustment in geriatric patients

Prolonged hypoglycemia has been reported with use; titrate dose cautiously; watch for hypoglycemic or hyperglycemic symptoms.

Type 2 Diabetes Mellitus 1 mg oral qDay; titrate dose weekly to avoid hypoglycemia.

Dose Adjustment in Kidney Impairment Patient:

Not studied; not recommended in severe impairment; initiate therapy with 1 mg PO qDay and titrate carefully

Dose Adjustment in Hepatic Impairment Patients:

Hepatic impairment: 1 mg oral qDay; titrate dose based on fasting blood glucose levels

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of glimepiride.

Overconsumption of Glimepiride could lead to symptoms such as mild to severe hypoglycaemia.

Management

There is no specific antidote or treatment for excessive intake of glimepiride. However, immediate medical attention is essential. Glimepiride should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

Mild episodes of hypoglycemia can be treated with oral glucose whereas severe hypoglycemia with seizure, coma, or neurological impairment can be treated with glucagon or intravenous (IV) glucose. In Severe hypoglycemic reactions, hospitalization may be necessary to monitor and treat the individual until their blood sugar levels are stable.

Management typically involves supportive measures and symptomatic treatment. The patient will also be continue to monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Pharmacodynamics:

Glimepiride enhances insulin granule production from pancreatic beta cells and increases insulin sensitivity in peripheral tissues, increasing peripheral glucose absorption and lowering plasma blood glucose and glycated haemoglobin (HbA1C) levels. A multicenter, randomized, placebo-controlled clinical trial assessed the efficacy of glimepiride (1-8 mg) as monotherapy titrated over ten weeks to placebo in T2DM participants not managed by diet alone. Fasting plasma glucose (FPG) was reduced by 46 mg/dL, post-prandial glucose (PPG) was reduced by 72 mg/dL, and HbA1c was reduced by 1.4% more than the placebo in this trial. In another randomized study of patients with T2DM who received either a placebo or one of three doses (1, 4, or 8 mg) of glimepiride over 14 weeks, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P 0.001) compared to placebo. The 4- and 8-mg doses of glimepiride were more efficacious than the 1-mg dose; however, the 4-mg dose gave almost maximal antihyperglycemic efficacy.

Pharmacokinetics:

Absorption

Glimepiride is entirely absorbed after oral dosing within 1 hour and has a linear pharmacokinetic profile. Peak plasma concentrations (Cmax) of glimepiride were attained 2 to 3 hours after a single oral dose in healthy participants and several oral doses in type 2 diabetes patients. Accumulation does not develop after numerous doses. When glimepiride was administered with meals, the duration to attain Cmax rose by 12%, while the mean and AUC (area under the curve) fell by 8 to 9%, respectively. In a pharmacokinetic investigation of Japanese patients with T2DM, Cmax values in once-daily dosages were higher than those in twice-daily doses. Following oral administration, the absolute bioavailability of glimepiride is reported to be complete.

Distribution

Following dosage, the volume of distribution in healthy participants was 8.8 L (113 mL/kg). Glimepiride has a plasma protein binding rate of more than 99.5%.

Vd: 8.8 L

Protein-bound: 99.5%

Metabolism

Glimepiride is said to be metabolized in the liver. Following an intravenous or oral dosage, glimepiride undergoes oxidative biotransformation mediated by the CYP2C9 enzyme to create a pharmacologically active primary metabolite, cyclohexyl hydroxymethyl derivative (M1). One or more cytosolic enzymes can further convert M1 to the inactive metabolite carboxyl derivative (M2). M1 preserved roughly one-third of its parent's pharmacologic action in an animal model, with a half-life of 3-6 hours. However, whether M1's glucose-lowering action is therapeutically relevant is still being determined.

Metabolized extensively by hepatic P450 enzyme CYP2C9 to less-active metabolites

Metabolites: Cyclohexyl hydroxy methyl derivative (M1; mildly active) and the carboxyl derivative (M2; inactive)

Elimination

When three healthy male individuals were given 14C-glimepiride orally, nearly 60% of the total radioactivity was recovered in the urine after seven days. M1 and M2 were responsible for 80-90% of the radioactivity collected in urine. M1:M2 ratio in urine was roughly 3:2 in two participants and 4:1 in one subject. In faeces, around 40% of the total radioactivity was recovered. M1 and M2 accounted for almost 70% of the radioactivity collected in faeces (the M1:M2 ratio was 1:3). No parent medication was found in the urine or faeces. There was no substantial biliary excretion of glimepiride or its M1 metabolite after treatment in subjects.

Half-life: 5-9 hr

Total body clearance: 47.8 mL/min

Excretion: Urine (60%); faeces (40%)

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