Glimepiride + Metformin + Pioglitazone

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

Glimepiride + Metformin + Pioglitazone has been approved for managing type 2 diabetes mellitus by controlling blood sugar levels.

Upon oral ingestion, glimepiride is absorbed in the gut, metabolized in the liver, and eliminated via 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 Glimepiride + Metformin + Pioglitazone is low blood glucose levels (hypoglycemia).

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

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

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

Glimepiride: ATP-sensitive potassium channels, made up of Kir6.2 and SUR subunits and essential for glucose-stimulated insulin secretion (GSIS), are activated by ATP and ADP in pancreatic beta cells. Reduced ATP: ADP causes the channel to open, which in turn causes insulin inhibition, K+ outflow, and cell hyperpolarization. By attaching to SUR1 and SUR2A subunits and blocking these channels, glimepiride increases insulin release by changing the conformation of these channels and ultimately increasing the activity of beta cells in secreting insulin.

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 (PPARgamma). Activation of nuclear PPARgamma 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 + Glimepiride + Pioglitazone work synergistically to manage type 2 diabetes effectively. They individually regulate blood sugar through diverse mechanisms, especially when single or dual therapy proves insufficient. Glimepiride, a sulfonylurea, boosts insulin release from the pancreas to lower blood glucose. Metformin, a biguanide, curbs liver glucose output, delays intestinal glucose absorption and enhances insulin sensitivity. Pioglitazone, a thiazolidinedione, further amplifies insulin sensitivity to maintain better blood sugar control in diabetes management collectively.

Glimepiride+ 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.

Glimepiride + Metformin + Pioglitazone can be used in the following health conditions:

Glimepiride: 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.

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 Glimepiride + Metformin + Pioglitazone provides several therapeutic advantages. This is managing high blood glucose levels by facilitating the removal of excess glucose through urine. They enhance the body's insulin response, which regulates blood glucose levels, preventing post-meal surges. Consistent use as prescribed is crucial in reducing the risk of severe diabetes-related complications like kidney damage, eye issues, nerve problems, and limb loss, emphasizing the importance of controlling blood glucose levels for effective diabetes management.

Orally: Glimepiride+ 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 3 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.

Glimepiride+ 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, such as 1 mg of glimepiride, and reassess in 2-4 weeks based on glycemic control.

Maintenance Therapy: If ideal glycemic control is attained, stick to the original dosage.

Transfer to larger dosages (e.g., 2 mg of Glimepiride) if the desired outcome is not achieved.

Individualized Dosage and Limitations: Adjust dosages based on gastrointestinal tolerance and effectiveness.

The maximum recommended daily doses for metformin (2000 mg/day, divided doses), glimepiride (8 mg/day), and pioglitazone (45 mg/day) should not be exceeded.

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

Glimepiride+Metformin + Pioglitazone is usually taken with meals to reduce the risk of gastrointestinal side effects and to ensure proper absorption.

Excessive alcohol consumption can potentiate the blood sugar-lowering effects of Glimepiride and increase the risk of hypoglycemia (low blood sugar).

Substitute processed carbohydrates with whole grains and up your consumption of fruits, vegetables, and fiber. 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 practicing 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.

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

During extreme stress like trauma or surgery, Glimepiride may disrupt glucose balance, requiring a temporary shift to insulin for metabolic control. Metformin accumulation due to sudden renal decline heightens lactic acidosis risk. Temporarily halt metformin during severe diarrhoea, vomiting, fever, or reduced fluid intake. Intravascular iodinated contrast agents may trigger contrast-induced nephropathy. Pause metformin before surgeries involving general, spinal, or epidural anaesthesia or imaging procedures. Use only under hospital, licensed physician, or lab guidance—resume usage only after 48 hours since renal function assessment.

Glimepiride: During the first few weeks of therapy, there is a higher chance of hypoglycemia, which calls for close observation. Hemolytic anaemia may result from the use of sulfonylurea medications in patients with G6PD deficiency.

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

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

Dizziness

Low blood glucose, or hypoglycemia (Glimepiride)

Headache

Flatulence (Metformin)

Infection of the upper respiratory tract (Pioglitazone)

Airway inflammation or bronchitis (Pioglitazone)

Nausea

Vomiting

Diarrhea

Flatulence

Edema (swelling)

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

There is insufficient, poorly controlled research on this combination of medication during pregnancy. The use of glimepiride in pregnant women is not well-studied; animal research suggests that the hypoglycemia effect of the drug may be harmful to reproduction. It is, therefore, discouraged when pregnant. Limited research suggests no increased risk of congenital disabilities when using metformin. There is not enough information on pioglitazone's safety in pregnancy from human trials, and greater doses may have negative consequences in animals. Because of the possible risks to the mother and fetus, glimepiride plus metformin plus pioglitazone should not be used while pregnant. It is advised to use insulin during pregnancy to maintain normal blood glucose levels and lower associated risks.

It is not known if breast milk contains glimepiride or any of its metabolites. Lactating rats secrete pioglitazone into their milk. It is not known if human milk secretes it. The Glimepiride Metformin and Pioglitazone combination is not advised for use in nursing women because to the high medication excretion in human milk. Studies conducted on nursing rats reveal that metformin is eliminated through milk, reaching concentrations similar to those found in plasma. Nursing mothers have not yet been the subject of these research.

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

Glimepiride + Metformin + Pioglitazone should only be taken in people with normal renal function since Metformin is known to be eliminated via the kidneys and because patients with impaired renal function are more likely to experience major adverse medication events. The combination of Glimepiride, Metformin, and Pioglitazone should be used cautiously as age increases because ageing is linked to decreased renal function. Renal function should be periodically monitored and given care when determining a dose.

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

The use of Glimepiride + Metformin + Pioglitazone is not recommended in patients with hepatic impairment.

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

Overconsumption of Glimepiride+ Metformin + Pioglitazone could lead to severe hypoglycemia, confusion, dizziness, seizures, rapid heartbeat, unconsciousness, and signs of kidney failure or lactic acidosis.

There is no specific antidote or treatment for excessive Glimepiride + Metformin + Pioglitazone intake. However, immediate medical attention is essential. Glimepiride + 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.

Glimepiride: Pharmacological characteristics indicate that Glimepiride is a hypoglycemic drug of the second generation of sulphonylureas. It induces insulin release from the pancreatic islet of Langerhans beta cells. Peripheral insulin sensitivity is also improved. Insulin dynamics are generally improved, and insulin release is potentiated.

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.

Glimepiride: Although Glimepiride is quickly and effectively absorbed, there can be a significant variation across and within individuals. After oral treatment, peak plasma concentrations usually appear 4-6 hours later.

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: Following the oral administration of pioglitazone, the Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours but does not change the extent of absorption (AUC).

Glimepiride: Glimepiride is extensively distributed throughout the body, primarily affecting red blood cells and plasma. With 94–98% bound to albumin, it has a high affinity for plasma proteins, where it binds most of the proteins.

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.

Glimepiride: Glimepiride undergoes significant hepatic metabolism. The amount of the oral dosage that remains unaltered in the urine is less than 1%. Metabolites comprise conjugates of glucuronic acid as well as oxidized and hydroxylated derivatives.

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.

Glimepiride: The kidneys (60–70%) and faeces (10–20%) are the primary systems that eliminate metabolites and conjugates.

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.