Glibenclamide(glyburide) + Metformin

Glibenclamide+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of second-generation sulfonylureas and biguanides.

Glibenclamide (glyburide) + Metformin is approved for treating type 2 diabetes mellitus in adults when dietary management and either agent alone do not result in adequate glycemic control.

Glibenclamide (glyburide) is rapidly absorbed from the gastrointestinal tract, undergoes hepatic metabolism, and is primarily eliminated through the kidneys. Metformin is absorbed in the small intestine, does not undergo hepatic metabolism, and is excreted unaltered in the urine.

The common side effect of Glibenclamide+ Metformin is low blood glucose levels (Hypoglycemia).

Glibenclamide+ Metformin is available as a tablet for convenient administration.

Glibenclamide+ Metformin is available in India, the United States, Canada, the United Kingdom, Germany, France and Australia.

Glibenclamide+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of second-generation sulfonylureas and biguanides.

Glibenclamide: These medications prevent pancreatic beta cells' ATP-sensitive potassium channels from opening. Sulfonylurea receptor 1 (SUR1) is the name for the ATP-sensitive potassium channels found on beta cells. Low glucose concentrations cause SUR1 to stay open, which permits potassium ion efflux to produce a membrane potential of -70 mV. High glucose concentrations typically cause SUR1 to close, the cell's membrane potential to lessen, the cell to depolarize, voltage-gated calcium channels to open, calcium ions to enter the cell, and an increase in intracellular calcium concentration that triggers the release of insulin-containing granules. By closing SUR1 and promoting enhanced insulin secretion, Glibenclamide circumvents this mechanism.

Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Synergistic Benefits: Metformin and Glibenclamide (often called glyburide) work synergistically to help manage type 2 diabetes. Metformin decreases glucose synthesis in the liver and increases insulin sensitivity, whereas Glibenclamide promotes the pancreas' insulin release. They improve total glycemic management by targeting various facets of glucose metabolism. This combination provides a thorough method of controlling blood sugar levels and reduces the risk of diabetes-related problems. It benefits patients whose blood sugar levels are poorly controlled with monotherapy.

Data Onset of action of Glibenclamide+ Metformin typically occurs within hours after administration.

Data duration of action of Glibenclamide+ Metformin effects generally sustained for several hours.

The Data of Tmax and Cmax of Glibenclamide+ Metformin is not established.

Glibenclamide+ Metformin 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 twice daily, generally with a meal.

Glibenclamide: Glibenclamide 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.

Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization.

Metformin + Glibenclamide (glyburide) combination provides therapeutic benefits for treating type 2 diabetes. Glibenclamide helps regulate blood sugar by stimulating the pancreas to secrete more insulin. Metformin decreases hepatic glucose synthesis, increases peripheral glucose absorption, and improves insulin sensitivity. Combined, they provide a synergistic approach to address several aspects of the pathophysiology of diabetes, effectively controlling blood sugar levels and lowering the risk of Hypoglycemia associated with Glibenclamide monotherapy.

Orally: Glibenclamide+ Metformin is available as a tablet that can be taken orally.

It is commonly taken twice daily with food to maximize its effectiveness in regulating blood sugar levels throughout the day. 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.

Glibenclamide + Metformin has various strengths, such as 1.25mg+ 250mg, 2.5mg+500mg or 5 mg+500mg.

Glibenclamide + Metformin is available in the form of Oral tablets.

Type 2 Diabetes Mellitus

1.25/250 mg metformin/glyburide PO once daily or every twelve hours; may titrate up every two weeks to a maximum of 20/2000 mg daily.

Glibenclamide + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.

Maintain adequate fluid intake to reduce the risk of dehydration and hypotension, especially in hot weather or during vigorous physical activity.

Limit consumption of alcohol as it can increase the risk of Hypoglycemia.

While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.

The dietary restriction should be individualized as per patient requirements.

Glibenclamide+ Metformin may be contraindicated in the following conditions:-

The adverse reactions related to Glibenclamide+ Metformin can be categorized as:-

In the digestive system, cholestatic jaundice and hepatitis can sometimes arise and lead to liver failure; stop taking medication.

Myalgia, arthralgia, angioedema, and vasculitis are examples of allergies.

Photosensitivity and Porphyria cutanea tarda are dermatological conditions.

Hematologic: Leukopenia, aplastic anaemia, thrombocytopenia, which can sometimes manifest as purpura, hemolytic anaemia, aplastic anemia, and pancytopenia

Metabolic: Disulfiram-like reactions in rare instances with glyburide; hepatic porphyria reactions reported with sulfonylureas but not with glyburide; hyponatremia cases reported most frequently in patients on other medications or with medical conditions known to cause hyponatremia or increase the release of antidiuretic hormone.

Abnormalities in liver function, such as isolated increases in transaminase.

The clinically relevant drug interactions of Glibenclamide and metformin are briefly summarized here:

Thiazides and other diuretics, thyroid products, estrogen, oral contraceptives, phenytoin, corticosteroids, phenothiazines, nicotinic acid, sympathomimetics, Ca channel blockers, and isoniazid may cause reduced glucose tolerance. Glibenclamide: Clifenclamide may amplify the hypoglycemic effect when combined with anabolic steroids, ciprofloxacin, sulfamethoxazole/trimethoprim combination, sulfonamides, tetracyclines, disopyramide, MAOIs, NSAIDs (like phenylbutazone), salicylates, coumarin derivatives, clofibrate, probenecid, ACE inhibitors (like captopril, enalapril), and salicylates. The signs of Hypoglycemia, including palpitations and tachycardia, may be concealed by β-blockers; nonetheless, most non-cardioselective β-blockers can potentially exacerbate and elevate Hypoglycemia. It may lessen the hypoglycemic impact of diazoxide and rifampicin. Increased fluconazole half-life. Decreased plasma concentration and exposure when using bile acid sequestrants (such as colesevelam); give Glibenclamide and metformin at least four hours before using bile acid sequestrants—diminished desmopressin's antidiuretic action.

Potentially fatal: Bosentan increases the risk of hepatotoxicity or increased liver enzymes. Miconazole (oromucosal gel, systemic method) may raise the risk of severe Hypoglycemia. When intravascular iodinated contrast agents are administered concurrently, lactic acidosis and renal failure may develop.

The most common side effects of Glibenclamide + Metformin include:

Glibenclamide+ Metformin should be prudent in the following group of special populations.

Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

However, sulfonylureas, which include glyburide, cross the placenta and have been linked to adverse reactions in newborns, such as Hypoglycemia; therapy should be stopped at least two weeks before the anticipated delivery date. The available data from a small number of published studies and postmarketing experience with glyburide use in pregnancy over decades has not identified any drug-associated risks for significant congenital disabilities, miscarriage, or adverse maternal outcomes.

When pregnancy is involved, poorly treated diabetes mellitus poses dangers to both the mother and the fetus. There is no conclusive evidence linking the use of metformin during pregnancy to a significant increased risk of miscarriage or congenital impairment in published research. Limited data on metformin in pregnant women are insufficient to determine a drug-associated risk for significant congenital disabilities or miscarriage.

Uncontrolled diabetes mellitus during pregnancy raises the risk of significant congenital disabilities, stillbirth, and morbidity related to macrosomia in the fetus. It also increases the risk of spontaneous abortions, preterm delivery, diabetic ketoacidosis, and delivery complications in the mother.

Pregnant patients treated with sulfonylureas for gestational diabetes may have a higher risk of admission to neonatal critical care, as well as an increased chance of respiratory distress, Hypoglycemia, birth trauma, and big size for gestational age; neonates born to mothers who were given a sulfonylurea at the time of delivery have been known to experience prolonged severe Hypoglycemia, which can last four to ten days; this condition has also been linked to the use of drugs with a longer half-life; Monitor for signs of Hypoglycemia and respiratory distress in neonates and adjust care accordingly.

At least two weeks before the anticipated birth date, medication should be stopped due to reports of sustained severe Hypoglycemia in newborns born to mothers using a sulfonylurea at the time of delivery.

In reproduction trials, glyburide doses up to 500 times the maximum human therapeutic dose of 20 mg, depending on body surface area, were given to rats and rabbits with no evidence of harm to the fetus.

When metformin was given to pregnant Sprague Dawley rats and rabbits during the organogenesis stage at dosages up to three and six times, respectively, a 2000 mg clinical dose, based on body surface area, no adverse developmental effects were seen.

Breastfed infants whose mothers are on therapy should be monitored for signs of Hypoglycemia; although one small clinical lactation study found that glyburide was hardly present in human milk, this finding is not definitive due to the limitations of the assay used in the study; no data exists regarding the effects of glyburide on milk production; few published investigations report that metformin is present in human milk; however, there is not enough information to determine the consequences of metformin on breastfed infants and no available data on the impacts of metformin on milk production; hence, the benefits of breastfeeding for development and health should be taken into consideration, as well as the mother's clinical need for therapy and any potential adverse effects on the breastfed child resulting from a medication or the underlying condition of the mother.

Monitor breastfed babies for hypoglycemia symptoms, such as jitters, cyanosis, apnea, hypothermia, excessive tiredness, poor feeding, seizures, etc.

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

1.25/250 mg metformin + glibenclamide PO every day or every twelve hours

Patients who are older than 80 years should not use this medication unless their renal function has been evaluated; do not titrate to the maximum dose. Instead, adjust carefully in these cases.

Before taking metformin, determine your eGFR.

Using an eGFR <30 mL/min/1.73 m² is not recommended. 0.3–45 mL/min/1.73 m²: Avoid starting treatment immediately.

For people at risk of renal impairment (such as the elderly), check their eGFR at least once a year or more regularly.

The risks and benefits of continuing medication should be assessed if eGFR falls below 45 mL/min/1.73 m² while on metformin.

Stop using metformin if your eGFR exceeds 30 mL/min/1.73 m².

Hepatic impairment: Avoid use; cases of lactic acidosis reported.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Glibenclamide+ Metformin.

Overconsumption of Glibenclamide+ Metformin could lead to mild to severe hypoglycemia lactic acidosis.

There is no specific antidote for Glibenclamide+ Metformin overdose, emphasizing the need for immediate medical attention. Suspected overdose warrants discontinuation of the medications.

If there are mild hypoglycemia symptoms, but no loss of consciousness or neurological signs, oral glucose and changes in medication dosage and/or meal schedules should be administered with vigor. Close observation should be maintained until the doctor specifies that the patient is not in danger. An IV infusion of 50% glucose solution or the administration of glucagon is necessary for severe hypoglycemic episodes that result in coma, seizures, or other neurological damage.

Hemodialysis may be an option in severe overdose, especially with acute kidney injury.

Patients must be constantly observed for at least 24 to 48 hours, as Hypoglycemia may recur after apparent clinical recovery.

Glibenclamide: Glibenclamide increases intracellular potassium and calcium ion concentrations by causing beta cells' ATP-sensitive potassium channels to close, promoting insulin production. Glibenclamide has a broad therapeutic index since patients can begin taking it at doses as little as once daily, and it has a lengthy duration of effect. As with tolbutamide, another sulfonylurea, Glibenclamide, should be used cautiously due to an elevated risk of cardiovascular mortality.

Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, reduces hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, unlike sulfonylureas, does not result in hyperinsulinemia or Hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.

Glibenclamide: After oral treatment, Glibenclamide is efficiently absorbed. Reaching peak plasma concentrations usually takes 4–6 hours, so the body can easily use it for the desired therapeutic purpose.

Bioavailability: Variable, depending on the oral dosage form

Onset: 15 to 60 min after a single dose (increase in serum insulin levels)

Duration: <24 hr

Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).

Bioavailability: 50-60% (Metformin [fasted])

Glibenclamide: Glibenclamide is mainly bound to plasma proteins and accumulates all over the body. It can enter target tissues and is found in the circulation, regulating blood sugar.

Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.

Protein-bound: Negligible (Metformin)

Glibenclamide: CYP3A4 is the primary metabolizer of Glibenclamide, with CYP2C9, CYP2C19, CYP3A7, and CYP3A5 following in order of preference.3,2 These enzymes metabolize glyburide to produce 4-trans-hydroxy cyclohexyl glyburide (M1), 4-cis-hydroxy cyclohexyl glyburide (M2a), 3-cis-hydroxy cyclohexyl glyburide (M2b), 3-trans-hydroxycyclohexyl glyburide (M3), 2-trans-hydroxy cyclohexyl glyburide (M4), and ethyl hydroxy cyclohexyl glyburide (M5).2. Not only is the parent molecule considered to be active but also the metabolites M1 and M2b.

Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.

Glibenclamide: Glibenclamide gets eliminated 50% in the urine and 50% in the faeces, compared to other sulfonylureas. The primary metabolite of Glibenclamide that is destroyed is 4-trans-hydroxyglyburide.

Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.