Glibenclamide + Metformin + Pioglitazone

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

Glibenclamide + Metformin + Pioglitazone has been approved for managing type 2 diabetes mellitus. It helps by controlling blood sugar levels when diet, exercise, or single-agent therapy fails to control them effectively.

Glibenclamide is absorbed in the gut when taken orally, reaching peak plasma levels within 4-6 hours, primarily bound to albumin and eliminated via the urine. Metformin is absorbed in the small intestine and excreted essentially unchanged through the kidneys. Pioglitazone is well absorbed after oral intake, metabolized in the liver, and eliminated through faeces and urine.

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

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

Glibenclamide+ Metformin + Pioglitazone is available in India, the United States, Canada, the United Kingdom, Germany, France, Japan, Brazil, South Africa, and Australia.

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

Glibenclamide: It prevents 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).

Pioglitazone: Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPAR gamma). Activation of nuclear PPAR gamma receptors influences the production of several gene products involved in glucose and lipid metabolism. PPAR gamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones, increasing sodium reabsorption.

Synergistic Benefits: Metformin + Glibenclamide + Pioglitazone work synergistically to manage type 2 diabetes effectively. Glibenclamide, a sulfonylurea, augments insulin release from the pancreas to lower blood glucose. Metformin, a biguanide, curtails liver glucose production, delays intestinal glucose absorption and heightens insulin sensitivity. Pioglitazone, a thiazolidinedione, additionally boosts insulin sensitivity. This combination offers improved glycemic control by employing varied mechanisms to regulate insulin release, glucose production, absorption, and sensitivity in the body, enhancing the management of type 2 diabetes.

Glibenclamide + Metformin + Pioglitazone 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 before meals or with a meal.

Glibenclamide + Metformin + Pioglitazone treats type 2 diabetes mellitus when diet, exercise, or single agents fail to adequately control blood sugar levels caused by the body's inability to utilize insulin to convert glucose into energy properly. This combination is used in managing the condition's symptoms.

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 lowers basal and postprandial plasma glucose, which enhances glucose tolerance. It works by delaying intestinal glucose absorption, improving insulin sensitivity by increasing peripheral glucose uptake and utilization and reducing hepatic glucose synthesis by blocking gluconeogenesis and glycogenolysis.

Pioglitazone: Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues vital for insulin action, such as fatty tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of several insulin-responsive genes involved in controlling glucose and lipid metabolism.

For those with type 2 diabetes, the antidiabetic combination of Glibenclamide + Metformin + Pioglitazone provides several therapeutic advantages. This combination helps to increase the excretion of glucose through the urine, thereby actively controlling elevated blood glucose levels. It improves insulin sensitivity, which controls blood sugar levels after meals. Maintaining consistent compliance with the recommended dosage reduces the chance of developing diabetic complications such as kidney damage, nerve and vision problems, and amputation of limbs. Regular use encourages a healthy, balanced lifestyle combined with exercise and a diet. To maintain stable blood sugar levels and lessen the severe problems linked to diabetes, regular use of this medicine is necessary.

Orally: Glibenclamide+ Metformin + Pioglitazone is available as a tablet that can be taken orally. It is advised to progressively raise the metformin dose at the beginning of treatment to reduce gastrointestinal adverse effects. Take the drug once daily along with food, and the maximum recommended daily amount in adults should not exceed three tablets. The tablet should not be crushed or chewed and should be taken as a

whole with water. Avoid breaking, crushing, dissolving, or chewing; swallow them whole with water or milk. The tablet strength determines the precise dosage. Do not double the next dose if missed; take it as soon as possible.

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

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

Initiation: Start treatment with a single tablet each day that has predetermined dosages of each component drug.

Start with smaller dosages and titrate based on glycemic control.

The correct and safe dosage of Glibenclamide + Metformin + Pioglitazone is based on individual health conditions and needs.

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

Putting half of the meal on starchy vegetables, 25% on proteins, and 25% on complete grains is recommended. Take advantage of extended periods between meals or snacks; keep regular meal intervals. Eat in consistent intervals. Avoid having a lengthy gap between meals and snacks.

The risks of lactic acidosis, which occurs when the body's level of lactic acid grows and impairs the operation of many organs, and hypoglycemia, a drop in blood sugar that can be deadly in some circumstances, are increased by excessive alcohol drinking.

Substitute processed carbohydrates with whole grains and up your consumption of fruits, vegetables, and fibre. Eat fewer meals high in saturated fat, such as samosas, pastries, chips, and crisps. For regular frying and cooking, use fatty oils high in omega-3, such as safflower, peanut, mustard, and palm oil. Reduce stress by practising yoga, meditation, or mindfulness to control blood sugar. Consider low-fat dairy items such as cheese, fat-free milk, and yoghurt.

The dietary restriction should be individualized as per patient requirements.

Glibenclamide+ Metformin + Pioglitazone may be contraindicated under the following conditions:-

An accumulation of lactic acid in the blood, known as "lactic acidosis," is a condition that can be caused by glibenclamide metformin + pioglitazone. Symptoms include vomiting, severe exhaustion, abdominal discomfort, and breathing difficulties. Since it poses a serious risk to life, prompt medical intervention is necessary. Since the kidneys and liver are essential for the body to expel excess lactic acid, inform the doctor if you have any serious issues with them. Drinking too much alcohol raises the likelihood of developing lactic acidosis. Thus, avoid doing so. It increases the risk of heart failure; therefore, individuals with heart conditions should use it with caution.

Glibenclamide: This medication may increase a woman's risk of bone fractures. Extended usage (more than 12 months) may increase the risk of bladder cancer. If you experience an increased need to urinate, blood in your urine, or abdominal pain, inform your doctor immediately right away. Take caution, as this drug may cause hypoglycemia or low blood sugar.

Metformin: Patients with hypothyroidism should have their thyroid-stimulating hormone (TSH) levels checked regularly. Serum levels of vitamin B12 have been found to decline with long-term metformin treatment.

Pioglitazone: Post-marketing instances of both lethal and nonlethal hepatic failure have been documented in pioglitazone-using patients. When treating patients with oedema, pioglitazone should be administered with caution. Diabetic individuals' post-marketing experiences have included reports of macular oedema. An ophthalmologist should examine diabetic patients' eyes frequently.

The adverse reactions related to Glibenclamide+ Metformin + Pioglitazone are as follows:

The clinically relevant drug interactions of Glibenclamide + Metformin + Pioglitazone are briefly summarized here:

The most common side effects of Glibenclamide+ Metformin + Pioglitazone include:

Low blood glucose, or hypoglycemia (Glibenclamide)

Headache

Flatulence (Metformin)

Infection of the upper respiratory tract (Pioglitazone)

Airway inflammation or bronchitis (Pioglitazone)

Nausea

Vomiting

Diarrhea

Blood in urine

Erectile dysfunction

Visual disorder

Anaemia, or reduced red blood cell count

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

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

Glibenclamide's use during pregnancy should consider potential benefits over fetal risks, as animal studies may not mirror human outcomes. Elevated blood glucose during pregnancy correlates with congenital disabilities. Reports suggest prolonged, severe hypoglycemia in newborns if mothers used sulfonylurea medication at delivery, especially those with longer half-lives. It's advisable to discontinue Glibenclamide two weeks before expected delivery if used during pregnancy.

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

According to recent data, there may be a link between elevated blood glucose levels during pregnancy and a higher risk of congenital disabilities. Most medical professionals advise using insulin to keep blood glucose levels as near to normal as feasible when pregnant. If metformin HCl is unnecessary, it is not advisable to use it during pregnancy because research on animal reproduction does not necessarily indicate human response.

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

There are no adequate and well-controlled studies of Pioglitazone in pregnant women. There are no adequate and well-controlled studies of Pioglitazone in pregnant women. At doses 10 to 40 times the maximum recommended human quantity, animal studies reveal increased rates of post-implantation loss, delayed development, lower fetal weights, and delayed parturition. Pioglitazone should only be used during pregnancy if the possible advantages outweigh the possible risks to the developing foetus.

It is unknown if breast milk contains Glibenclamide or any metabolites. Lactating rats secrete pioglitazone into their milk. It is not known if human milk secretes it. The Glibenclamide+ Metformin + Pioglitazone combination is not advised in nursing women because of the high medication excretion in human milk. Studies conducted on nursing rats reveal that milk eliminates metformin, reaching concentrations similar to those in plasma. Nursing mothers have yet to be the subject of this research.

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

Little information is available regarding the safety and effectiveness of Glibenclamide + Metformin + Pioglitazone in the elderly population. Because of the possible age-related changes in medication metabolism, the reduction in renal function, and the increased risk of side effects, caution is suggested. To ensure patient safety and maximize treatment outcomes, older patients must be closely monitored for hypoglycemia, fluid retention, heart failure, and other drug-related adverse effects.

The use of Glibenclamide + Metformin + Pioglitazone is contraindicated in patients with renal impairment. Regular assessment of renal function is necessary.

It should be taken with caution in patients with diseases/conditions. The dose may need to be adjusted. Avoid use in cases of severe liver illness.

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

Overconsumption of Glibenclamide+ Metformin + Pioglitazone could lead to severe hypoglycemia, confusion, dizziness, seizures, rapid heartbeat, and unconsciousness, posing a risk of life-threatening complications like kidney failure and lactic acidosis.

There is no specific antidote or treatment for excessive Glibenclamide + Metformin + Pioglitazone intake. However, immediate medical attention is essential. Glibenclamide + Metformin + Pioglitazone should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal can be administered to reduce absorption if the ingestion is recent.

In mild cases, glucose administration or oral intake of carbohydrates helps elevate blood sugar levels. Severe hypoglycemia might require intravenous administration of glucose or glucagon.

If lactic acidosis is suspected due to metformin, provide aggressive treatment, including hemodialysis if needed. Monitor closely for 24 to 48 hours due to potential recurrence. Monitor for lactic acidosis with metformin until patient safety is confirmed.

Supportive care may involve the use of antiemetic medications to address nausea and vomiting, along with implementing measures to relieve abdominal discomfort. Hemodialysis is ineffective for clearing these medications due to their high protein binding and extensive metabolism.

Glibenclamide: By blocking the ATP-sensitive potassium channels in beta cells, Glibenclamide raises the amounts of potassium and calcium ions inside the cell, stimulating insulin generation. Patients can start taking glibenaclide at doses as little as once daily and its effects last a considerable amount of time, so it has a broad therapeutic index. Glibenclamide, another sulfonylurea, should also be used with caution because of an increased risk of cardiovascular mortality, similar to tolbutamide.

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.

Pioglitazone: An agonist for peroxisome proliferator-activated receptor-gamma (PPARγ) is pomiglitazone. Tissues crucial for insulin action, including skeletal muscle, the liver, and adipose tissue, contain PPAR receptors. The transcription of several insulin-responsive genes involved in the regulation of glucose and metabolism of lipids is modulated by the activation of PPARγ nuclear receptors.

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.

Metformin: Incompletely and slowly absorbed from the digestive system. Food reduces and delays absorption slightly. Complete bioavailability: 50%–60%. Time to peak plasma concentration: 2–3 hours (for rapid release); 4–8 hours (for delayed release); 7 hours.

50–60% bioavailability (metformin [fasted])

Pioglitazone: Pioglitazone's Tmax occurred two hours after oral treatment. Food does not alter the level of absorption (AUC). However it does cause the Tmax to be delayed by three to four hours.

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)

Pioglitazone: After a single dose, the mean apparent volume of distribution (Vd/F) of pioglitazone is 0.63 ± 0.41 (mean ± SD) L per kg of body weight. In human serum, pioglitazone is highly protein bound (>99%), primarily to serum albumin. Although with less affinity, pioglitazone also binds to other serum proteins. Additionally, M-III and M-IV have strong bindings (>98%) to serum albumin.

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.

Pioglitazone: Pioglitazone undergoes significant hydroxylation and oxidation-based metabolism. Part of the metabolites is converted to glucuronide or sulfate conjugates. The two primary active metabolites in human circulation are M-III and M-IV.

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.

Pioglitazone: After oral administration, approximately 15% to 30% of the pioglitazone dosage is reabsorbed in the urine. Pioglitazone is eliminated chiefly as metabolites and their conjugates, with very little renal clearance occurring. Most oral doses are thought to be removed in the faeces or excreted into the bile in its original form or as metabolites. Pioglitazone and its metabolites, M-III and M-IV, have respective mean serum half-lives (t1/2) of three to seven hours and sixteen to twenty-four hours. The apparent clearance (CL/F) of pioglitazone is estimated to be five to seven L/hr.