Metformin+ Pioglitazone
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Biguanide, Thiazolidinedione, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, India, the United Kingdom, Canada, Australia, Africa and various European and Asian countries.
Metformin + Pioglitazone is an Anti-diabetic Agent belonging to the pharmacological class of biguanide and Thiazolidinediones.
Metformin + Pioglitazone is approved for treating type 2 diabetes mellitus in adults. It is an oral medication that helps control blood sugar levels by increasing insulin sensitivity and reducing glucose production in the liver.
Metformin is absorbed in the upper small intestine, reaches peak plasma levels within 2-3 hours, and has an elimination half-life of about 6 hours. Pioglitazone is absorbed slowly, reaching peak plasma levels in about 2 hours. It has a long elimination half-life of 3 to 7 hours. Both the drugs are extensively metabolized in the liver and excreted in the urine.
The common side effects of Metformin + Pioglitazone are nausea, vomiting, diarrhoea, flatulence, and constipation.
Metformin + Pioglitazone is available as tablets for convenient administration.
Metformin + Pioglitazone is available in the United States, India, the United Kingdom, Canada, Australia, Africa and various European and Asian countries.
Metformin + Pioglitazone is an Anti-diabetic Agent belonging to the pharmacological class of biguanide and Thiazolidinediones.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
The onset of action of metformin was up to 2 weeks.
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: A combination of pioglitazone and metformin improves type 2 diabetes treatment. Metformin increases peripheral tissue insulin sensitivity while lowering the liver's synthesis of glucose. While reducing liver glucose production, pioglitazone improves muscle and fat cells' sensitivity to insulin. This synergistic action effect helps in more efficient blood sugar reduction.
Data Onset of action of Metformin + Pioglitazone is typically within a few hours after taking the medication.
Data duration of action of metformin + Pioglitazone needs to be better established.
The Data of Tmax and Cmax Metformin + Pioglitazone needs to be better established.
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, generally with a meal.
Metformin + Pioglitazone combination helps control blood sugar levels by improving insulin sensitivity and reducing excessive glucose production by the liver. It is used as an adjunct to diet and exercise in patients whose diabetes is inadequately controlled with metformin or pioglitazone alone.
Metformin + Pioglitazone is an Anti-diabetic Agent belonging to the pharmacological class of biguanide and Thiazolidinediones.
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.
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.
Metformin + Pioglitazone is a combination medication which is used to manage type 2 diabetes. It has several benefits, such as better blood sugar regulation through lowering insulin resistance, encouraging muscle uptake of glucose, and reducing the amount of glucose produced by the liver. When monotherapy is insufficient, this combination is frequently helpful in helping patients maintain better glucose control and may even lower their risk of complications from uncontrolled diabetes.
When treating individuals with type 2 diabetes mellitus with pioglitazone and metformin, pioglitazone and metformin hydrochloride tablets are advised as an addition to diet and exercise to enhance glycemic control.
Important Usage Limitations
- Only when endogenous insulin is present may pioglitazone reduce blood sugar levels. It is not recommended to treat type 1 diabetes or diabetic ketoacidosis with pioglitazone and metformin hydrochloride tablets as they are ineffective in these conditions.
- Patients with hepatic problems should exercise caution.
Orally: Metformin+ Pioglitazone is available as a tablet that can be taken orally. Metformin + Pioglitazone should be taken with food, and 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.
Metformin + Pioglitazone has various strengths, such as 500mg+15mg, 850mg+15mg, 1000mg+15mg, 1000mg + 30mg
Metformin + Pioglitazone is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
When starting metformin therapy, patients on metformin monotherapy should also take 15–30 mg of pioglitazone daily.
Individuals receiving pioglitazone monotherapy: 1000–1700 mg of metformin per day in addition to the pioglitazone dosage prescribed at the beginning of treatment.
No more than 45 mg pioglitazone and 2550 mg metformin per day.
Metformin + Pioglitazone should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Avoid excessive alcohol consumption, which may increase the risk of lactic acidosis when taking metformin.
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.
Avoid excessive grapefruit and grapefruit juice, as it may interact with the medication.
The dietary restriction should be individualized as per patient requirements.
Metformin + Pioglitazone may be contraindicated in the following conditions: -
- Hypersensitivity
- eGFR <30 ml/min/1.73 m² indicates severe renal disease.
- Metabolic acidosis, either acute or chronic, including DKA with or without coma
- Heart Failure Class III or IV in the NYHA
- When patients receive iodinated contrast agents for radiologic tests, temporarily stop using them.
- Patients 80 years of age or older should not be started. CrCl indicates that renal function is not compromised because lactic acidosis is more likely to occur in these patients.
- Stop using metformin if you have any conditions linked to hypoxemia, dehydration, or sepsis.
- Any diabetic patient with metabolic acidosis who does not exhibit signs of ketoacidosis (ketonuria and ketonemia) should be suspected of having lactic acidosis; this condition is a medical emergency that has to be treated in a hospital.
- Pioglitazone may aggravate pre-existing heart failure and result in fluid retention.
- Edema: dose-related fluid retention may result with thiazolidinediones peroxisome proliferator-activated receptor (PPAR) gamma agonists, especially when combined with insulin.
- Considering pioglitazone only has an antihyperglycemic effect when insulin is present, it should not be used to treat diabetic ketoacidosis or type 1 diabetes.
- It may result in hypoglycemia; people undergoing treatment with insulin or other anti-diabetic drugs (especially insulin secretagogues like sulfonylureas) may be susceptible to hypoglycemia. To lower the chance of hypoglycemia, the concurrent anti-diabetic medication's dosage may need to be reduced. Inadequate calorie intake or excessive exercise to offset the loss of calories can also result in hypoglycemia; hypoglycemia can be hard to diagnose in the elderly and patients on beta-adrenergic blocking medications.
- Sporadic cases of hepatic failure with or without a fatal outcome, as well as infrequent reports of hepatitis and hepatic enzyme increases to >3 xULN
- There have been reports of a decrease to subnormal levels of previously normal serum vitamin B12 levels in metformin-controlled clinical trials without any accompanying clinical manifestations. Some people (those with insufficient calcium absorption or intake) are more likely to develop subnormal vitamin B12 levels; in these patients, routine serum vitamin B12 measurements at intervals of two to three years may be helpful.
- The kidney primarily eliminates metformin, and the degree of renal impairment raises the risk of metformin buildup and lactic acidosis.
- It is not advised to use metformin therapy in patients with hepatic impairment as it has been linked to lactic acidosis in certain circumstances.
- Inform premenopausal women about the possibility of an unplanned pregnancy because metformin and pioglitazone medication may cause ovulation in certain anovulatory women.
- Cancer risk: There may be a higher risk of bladder cancer when taking pioglitazone. Those with still active bladder cancer shouldn't be prescribed it. Patients with a history of bladder cancer should take caution when using it, and they should notify their doctor immediately if they see any symptoms, such as blood in the urine, that could indicate bladder cancer.
- Iodinated contrast imaging procedures: When undergoing an iodinated contrast imaging technique, stop taking metformin if you have an eGFR of 30 to 60 mL/minute/1.73 m², if you have a history of liver disease, alcoholism, or heart failure, or if you will be receiving intra-arterial iodinated contrast.
Alcohol Warning
It is unsafe to consume metformin + Pioglitazone with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Metformin+ Pioglitazone in breastfeeding.
Pregnancy Warning
Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.
Food Warning
Increase intake of fibre-rich foods and minimize the carbohydrate or sugary intake.
The adverse reactions related to metformin + Pioglitazone can be categorized as:-
- Common Adverse Effects: Lower limb oedema, upper respiratory tract infection.
- Less Common Adverse Effects: Weight gain, diarrhoea, nausea, Urinary tract infection, dizziness, headache, sinusitis or oedema
- Rare Adverse Effects: Lactic acidosis, a rare but severe side effect linked to metformin, hypoglycemia and allergic reactions.
Reports on Postmarketing
Hepatitis with elevated liver enzymes to >3 XUL, including extremely uncommon cases of both fatal and non-fatal liver failure
Hepatocellular, mixed hepatocellular, and cholestatic liver damage
The clinically relevant drug interactions of Metformin + Pioglitazone are briefly summarized here:
- Potent CYP2C8 Inhibitors: The half-life (t½) and exposure (area under the serum concentration-time curve, or AUC) of pioglitazone is considerably increased by CYP2C8 inhibitors, such as gemfibrozil. Thus, when administered with gemfibrozil or other potent CYP2C8 inhibitors, the highest recommended dosage of pioglitazone is 15 mg daily.
- CYP2C8 Inducers: Pioglitazone improves peripheral tissue insulin sensitivity, enabling more effective blood sugar regulation, whereas metformin decreases the liver's ability to produce glucose.
- Carbonic Anhydrase Inhibitors: For example, zonisamide, acetazolamide, dichlorphenamide, or topiramate are examples of other carbonic anhydrase inhibitors that can reduce serum bicarbonate levels and create hyperchloremic, non-anion gap metabolic acidosis. A higher risk of lactic acidosis may result from concurrent use of these medications with pioglitazone and metformin hydrochloride. Consider monitoring these patients more frequently.
- Drugs that Reduce Metformin Clearance: The concurrent use of medications that disrupt the standard renal tubular transport systems involved in the elimination of metformin by renal (e.g., multidrug and toxin extrusion [MATE] inhibitors, ranolazine, vandetanib, dolutegravir, and cimetidine) may raise the risk of lactic acidosis as well as increase systemic exposure to metformin. Evaluate the advantages and disadvantages of using concurrently.
- Insulin Secretagogues or Insulin: A patient receiving pioglitazone, metformin hydrochloride, and an insulin secretagogue (such as sulfonylurea) concurrently should have their dose of the insulin secretagogue lowered if hypoglycemia develops. When a patient receives insulin, metformin hydrochloride, and pioglitazone simultaneously and has hypoglycemia, the dosage should be reduced by 10% to 25%. The glycemic response should be considered when making additional insulin dose modifications.
- Alcohol: It is well known that alcohol increases the way that metformin affects lactate metabolism. Patients using pioglitazone and metformin hydrochloride should be cautioned against consuming large amounts of alcohol.
- Drugs Affecting Glycemic Control: Certain medications can cause hyperglycemia, impairing glycemic control. These medications include corticosteroids, phenothiazines, thyroid products, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, thiazides and other diuretics, estrogens, and oral contraceptives. Patients on pioglitazone and metformin hydrochloride who are given such medications should be regularly monitored for any loss of blood glucose control. When patients using pioglitazone and metformin hydrochloride have such drugs stopped, they should be closely monitored for hypoglycemia.
The most common side effects of Metformin + Pioglitazone include:
- diarrhea
- nausea
- upset stomach.
- cold-like symptoms (upper respiratory tract infection)
- swelling in the feet (edema)
- headache legs, or ankles
- weight gain
Metformin + Pioglitazone should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category C: Use with caution if the benefits outweigh the risks.
There is insufficient data about using metformin/pioglitazone or pioglitazone in pregnant women to establish a drug-associated risk for severe birth abnormalities or miscarriage. Maternal risks associated with poorly managed diabetes during pregnancy include diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirths, and delivery complications; fetal hazards include significant congenital disabilities, stillbirths, and morbidity related to macrosomia.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
The risk of diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery difficulties is higher in mothers with poorly controlled diabetes during pregnancy. The risk of severe birth abnormalities, stillbirth, and morbidity associated with macrosomia increases in a fetus with poorly controlled diabetes.
Human Data
The use of metformin during pregnancy has not been linked to significant birth abnormalities, miscarriage, or unfavourable outcomes for either mother or fetus, according to published data from postmarketing studies. However, due to methodological issues such as small sample sizes and uneven comparator groups, these studies cannot conclusively show any danger linked with metformin.
Animal Data
Metformin Hydrochloride and Pioglitazone
Studies involving animal reproduction have yet to be carried out using the combination of pioglitazone and metformin hydrochloride. The following information is based on research using metformin hydrochloride and pioglitazone as separate substances.
- Nursing Mothers
The detection of pioglitazone or metformin/pioglitazone in human milk, effects of this drug combination on breastfed infants, or its impact on the milk production are all unknown. Metformin results on breastfed infants need to be better understood, and there is no current evidence about the drug's effect on milk production. The advantages of nursing for development and health should be considered, as well as the mother's clinical requirement for medication and any possible side effects from metformin or pioglitazone or an underlying medical condition on the breastfed baby.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
- Geriatric Use
The safety and efficacy of metformin + pioglitazone in the elderly population (65 years of age and older) have not been well investigated. Age-related changes in liver and renal function may make older people more vulnerable to adverse effects. Cautious observation is required, and dosage modifications can be necessary depending on each patient's health condition and response.
Dosage adjustment in geriatric patients
Type 2 Diabetes Mellitus (Refer adult dosing)
Do not administer to patients over 80 years before assessing renal function and determined to be normal.
Dose Adjustment in Kidney Impairment Patient:
Before beginning metformin, determine eGFR.
eGFR <30 mL/min/1.73 m²: Not recommended 1.73 m²/min or 30-45 mL/min: Not advised to start a treatment.
Monitor eGFR at least once a year or more frequently if you are at risk of renal impairment (older people).
When taking metformin, if eGFR drops below 45 mL/min/1.73 m², the risks and benefits of continuing medication should be assessed.
Stop taking metformin once the eGFR drops to less than 30 mL/min/1.73 m².
Dose Adjustment in Hepatic Impairment Patients:
Baseline ALT <2.5 xULN: Continue with caution
ALT baseline ≥2.5 xULN: Avoid starting
ALT >3 xULN or jaundice after starting treatment: Discontinue
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Metformin + Pioglitazone.
Overconsumption of Metformin + Pioglitazone could lead to hypoglycemia symptoms such as shakiness, sweating, confusion, and, in severe cases, seizures or loss of consciousness.
Management
There is no specific antidote or treatment for excessive intake of metformin + pioglitazone. However, immediate medical attention is essential. Metformin+ Pioglitazone 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 effectively 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, oxygen therapy, intravenous fluids to maintain blood pressure and symptomatic treatment. The patient will also continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.
Pharmacodynamics
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.
Pharmacokinetics
Absorption
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])
Pioglitazone: Following the oral administration of pioglitazone, 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).
Distribution
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/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.
Metabolism
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.
Elimination
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.
Therapeutic benefits of a combination of metformin + Pioglitazone
Pioglitazone assist the body to use insulin more effectively by particularly addressing insulin resistance. This combination can improve metabolic health and glucose utilization by lowering insulin resistance.
Metformin and pioglitazone together provide an efficient way to reduce blood glucose levels. While pioglitazone improves insulin sensitivity in peripheral tissues, metformin decreases the liver's ability to produce glucose, improving blood sugar control.
It may offer cardiovascular benefits by improving lipid profiles, reducing inflammation, and potentially lowering the risk of heart disease in diabetic individuals.
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Published on: 26 Oct 2023 5:25 AM GMT