Gliclazide + Metformin + Pioglitazone

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

Gliclazide + Metformin + Pioglitazone has been approved for managing type 2 diabetes mellitus.

Gliclazide is absorbed well, primarily metabolized in the liver, and eliminated through urine and faeces. 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 Gliclazide + Metformin + Pioglitazone is low blood glucose levels (hypoglycemia).

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

Gliclazide+ Metformin + Pioglitazone is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, Italy, Spain, and Australia.

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

Gliclazide: The sulfonylurea drug gliclazide works by attaching itself to the pancreatic beta cells' SUR1 sulfonylurea receptor. Potassium efflux is stopped by this binding, which blocks ATP-sensitive potassium channels. The beta cells, therefore, experience depolarization. The beta cells' voltage-dependent calcium channels open in response to this depolarization. An increase in calcium causes the calcium-binding protein calmodulin to become active, which sets off a series of actions that eventually result in the exocytosis of insulin-containing secretory granules. When insulin is released into the bloodstream, cells are more likely to absorb glucose, lowering blood sugar levels in people with diabetes.

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 + Gliclazide + Pioglitazone work synergistically to manage type 2 diabetes effectively. When single or dual therapies fail, they collectively regulate blood sugar through diverse mechanisms. Gliclazide, a sulfonylurea, boosts insulin release from the pancreas, while pioglitazone, a thiazolidinedione, enhances insulin sensitivity. Metformin, a biguanide, reduces liver glucose production, delays intestinal glucose absorption, and improves the body's insulin sensitivity.

Gliclazide+ 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.

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

Gliclazide: Gliclazide 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, enhancing 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 Gliclazide + Metformin + Pioglitazone provides several therapeutic advantages. Gliclazide boosts insulin production from the pancreas, while Metformin curtails liver glucose production and intestinal glucose uptake. Pioglitazone contributes by lowering liver glucose release and improving tissue sensitivity to insulin. This combination effectively regulates post-meal blood sugar levels alongside diet and exercise, averting complications like kidney damage, vision loss, and nerve damage. Additionally, it lowers the risk of heart-related issues, simplifying medication routines by amalgamating multiple benefits into a single drug regimen.

Orally: Gliclazide+ 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 along with food. Avoid breaking, crushing, dissolving, or chewing; swallow them whole with a glass of 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.

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

For patients with insufficient control of sulfonylurea or metformin, Pioglitazone can start at 15 or 30 mg once daily. If the response remains inadequate, the dosage may incrementally rise, reaching up to 45 mg once daily.

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

Gliclazide+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 Gliclazide and increase the risk of hypoglycemia (low blood sugar).

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.

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

Hypoglycemia may occur if the patient cuts down on their dietary intake if they overdose on purpose or accidentally, or if they have severe physical activity, trauma, or stress. A diabetic meal plan might help lessen the symptoms of hypoglycemia. If hypoglycemia signs and symptoms appear, prompt action should be taken.

Modify the combination's dosage based on blood and urine glucose levels during the first several months. Few instances of lactic acidosis in people with liver or kidney illness have been documented, nevertheless.

There is insufficient scientific evidence regarding the use and safety of Gliclazide+ Metformin + Pioglitazone in breastfeeding.

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

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

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

Dizziness

Low blood glucose, or hypoglycemia

Headache

Infection of the upper respiratory tract

Airway inflammation, or bronchitis

Nausea

Vomiting

Diarrhea

Flatulence

Edema (swelling)

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

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

Elevated blood glucose levels during pregnancy increase the risk of congenital abnormalities. Insulin is typically recommended to maintain near-normal blood glucose levels. However, the use of Gliclazide, Metformin, and Pioglitazone combination is not advised during pregnancy due to potential risks.

It is unknown whether Gliclazide or its metabolites are excreted in breast milk. Pioglitazone is secreted in the milk of lactating rats. It is unknown whether it is secreted in human milk. Because many drugs are excreted in human milks, the use of the Gliclazide Metformin and Pioglitazone combination is not recommended for use in lactating mothers. Research on lactating rats indicates that Metformin is excreted into milk and reaches levels comparable to plasma. These studies have yet to be done on nursing mothers.

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

Gliclazide + 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 Gliclazide, 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 Gliclazide + Metformin + Pioglitazone is contraindicated in patients with renal impairment.

Regular assessment of renal function is necessary.

The use of Gliclazide + 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 Gliclazide+ Metformin + Pioglitazone.

Overconsumption of Gliclazide+ Metformin + Pioglitazone could lead to hypoglycemia (low blood sugar), nausea, vomiting, abdominal discomfort, and lactic acidosis.

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

For hypoglycemia (low blood sugar), consume a source of rapidly absorbed carbohydrates such as glucose tablets, sugar, or honey. Monitor blood glucose levels and repeat treatment if necessary.

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. In severe cases, medical professionals may consider hemodialysis or other appropriate interventions based on the severity of the overdose and the individual's condition

Gliclazide: Pharmacological characteristics indicate that gliclazide 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.

Gliclazide: Although gliclazide 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).

Gliclazide: Gliclazide 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.

Gliclazide: Gliclazide 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.

Gliclazide: 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.