Glimepiride + Metformin
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:
Sulfonylureas, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
India, the United States, Canada, the United Kingdom, Germany, Japan, France and Australia.
Glimepiride+ Metformin is an anti-diabetic agent belonging to the pharmacological class of second-generation sulfonylureas and biguanides.
Glimepiride+ Metformin has been approved as a treatment for type 2 diabetes mellitus, helping to control blood sugar levels in those individuals with diabetes by improving insulin sensitivity and reducing the production of glucose in the liver.
Glimepiride is rapidly absorbed, undergoes metabolism in the liver, and is excreted mainly in the urine. Metformin is absorbed in the upper gastrointestinal tract, does not undergo hepatic metabolism, and is excreted unchanged in the urine.
The common side effect of Glimepiride+ Metformin is low blood glucose levels (hypoglycemia).
Glimepiride+ Metformin is available as a tablet for convenient administration.
Glimepiride+ Metformin is available in India, the United States, Canada, the United Kingdom, Germany, Japan, France and Australia.
Glimepiride+ Metformin is an Anti-diabetic Agent belonging to the pharmacological class of second-generation sulfonylureas and biguanides.
Glimepiride: Intracellular ATP and ADP activate pancreatic beta cell ATP-sensitive potassium channels. The channel's hetero-octomeric complex comprises four pore-forming Kir6. 2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing enables the creation of channels of distinct subunit isoforms expressed at various amounts in different organs. ATP-sensitive potassium channels are critical metabolic sensors and regulators in pancreatic beta cells, coupling membrane excitability with glucose-stimulated insulin secretion (GSIS). When the ATP: ADP ratio decreases, the channels are activated and open, resulting in K+ outflow from the cell, membrane hyperpolarization, and inhibition of insulin secretion.On the other hand, increased glucose uptake into the cell causes an increase in the intracellular ATP: ADP ratio, which causes channel closure and membrane depolarization. Depolarization causes activation and opening of voltage-dependent Ca2+ channels, resulting in an influx of calcium ions into the cell. Increased intracellular calcium levels induce the actomyosin filaments responsible for the exocytosis of insulin granules contained in vesicles to contract. Glimepiride inhibits the ATP-sensitive potassium channel by binding non-specifically to the B sites of the sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits, as well as the A site of SUR1 subunit of a channel to boost insulin secretion from the beta cell.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Synergistic Benefits: Glimepiride + metformin combination has synergistic effects on type 2 diabetes management. Glimepiride helps the body use glucose by stimulating the pancreas to secrete more insulin, and metformin reduces the amount of glucose produced by the liver while increasing peripheral insulin sensitivity. Combined, they provide complete glycemic control by addressing insulin sensitivity and secretion. By optimizing blood glucose levels, this dual process helps to enhance diabetes control. By reducing the need for higher doses of each component and improving efficacy, the synergistic effects help minimize the risk of adverse effects.
Glimepiride+ 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 three times daily before meals or generally with a meal.
Glimepiride+ Metformin can be used in the following health conditions:
- Treatment for individuals with type 2 diabetes mellitus when glycemic control is inadequate with diet and exercise alone.
- It may also be considered in managing polycystic ovary syndrome to help regulate menstrual cycles and address metabolic aspects.
- Prevention of diabetic complications such as cardiovascular issues, kidney problems, and nerve damage.
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. It often only causes a single frequent adverse effect and is taken once each day.
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 + glimepiride is used to treat type 2 diabetes. The pancreatic cells that generate insulin are stimulated by glimepiride, which helps remove sugar from the circulation. Metformin is an approved drug with a prolonged half-life that delivers the medication gradually over an extended period. Metformin inhibits the liver's cells' ability to produce sugar and postpones the intestines' ability to absorb sugar. Additionally, it makes muscle cells more sensitive to insulin, which improves their ability to eliminate sugar from the blood.
Glimepiride + metformin is indicated as an adjunct to diet and exercise in patients with type-2 diabetes who are not responding well to metformin alone, who are already receiving treatment with glimepiride and metformin, or who have responded well to glimepiride alone but require further glycemic control.
Orally: Glimepiride+ Metformin is available as a tablet that can be taken orally.
It is advised to administer once daily during breakfast or the first main meal and avoid breaking, crushing, dissolving, or chewing extended-release pills; swallow them whole with a glass of water. If a dose is missed, the individual should take it promptly upon recall. If the missed dose coincides with the upcoming scheduled dose, it is advisable to skip the missed dose and proceed with the regular schedule. Discontinuation of the medication should only occur under medical guidance to prevent fluctuations in blood sugar levels.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Glimepiride+ Metformin has various strengths, such as 0.5mg+ 500mg, 0.5 mg+1000mg, 1mg+ 500mg, 1 mg+850mg, 1mg+1000mg, 3mg+850mg, 2mg+500mg, 2 mg+ 850mg, 2 mg+1000mg, 3mg+850mg, 3mg+1000mg, 4 mg+ 1000mg.
Glimepiride+ Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
The combination should be given once daily with meals and started at a low dose.
Initial dose for individuals whose metformin monotherapy is not sufficiently controlled
After assessing the therapeutic response, glimepiride + metformin may be initiated once a day and titrated gradually.
The initial dose for individuals who showed improvement with glimepiride monotherapy and require additional glycemic management
Glimepiride + metformin may be started once daily and titrated gradually after evaluating the therapeutic response, depending on the initial beginning dose of glimepiride (1 or 2 mg).
The initial dose for individuals switching from glimepiride plus metformin combination therapy as separate tablets may be determined by their current dose of glimepiride and metformin.
Maximum Recommended Dosage: Eight milligrams per day is the maximum recommended dose of glimepiride. The highest recommended daily dosage of metformin sustained release for adults is 2000 mg.
Glimepiride+ Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Glimepiride + Metformin is usually taken with meals to lower the risk of gastrointestinal side effects and to ensure proper absorption.
Limit or avoid alcohol while taking Glimepiride and Metformin, as alcohol can potentiate the risk of hypoglycemia (low blood sugar).
Individuals should follow a diet that is low in fat and sugar. This involves substituting carbohydrates with whole grains, fruits, and vegetables, as carbohydrates can be converted into sugars, resulting in elevated blood sugar levels. High glycemic foods like potatoes should be avoided due to its potential to raise blood sugar.
The dietary restriction should be individualized as per patient requirements.
Glimepiride+ Metformin may be contraindicated under the following conditions: -
- Glimepiride + metformin is contraindicated for the treatment of diabetic ketoacidosis, diabetic precoma or coma, or insulin-dependent (type I) diabetes mellitus (e.g., people with diabetes with a history of ketoacidosis).
- In patients hypersensitive to glimepiride, other sulfonylureas, other sulfonamides, or any excipients (risk of hypersensitivity reactions), glimepiride+Metformin should not be taken.
- The use of Glimepiride + Metformin in individuals undergoing dialysis or with severe liver impairment has not been studied. It is recommended that patients with severe impairments to their liver or kidneys switch to insulin, if only to ensure the best possible metabolic management.
- Hypoglycemia: Glimepiride + Metformin should be used cautiously as it may result in hypoglycemia or low blood sugar. Monitor the blood sugar levels frequently, especially if it's on insulin or other antidiabetic medications. To treat low blood sugar, ensure that individuals have access to a source of glucose, such as glucose tablets.
- Gastrointestinal Effects: Glimepiride is associated with common gastrointestinal side effects such as diarrhoea, flatulence, and discomfort in the abdomen. These symptoms are usually temporary. If severe symptoms persist, consulting a medical expert is recommended.
- Lactic Acidosis: Metformin may cause lactic acidosis, an unusual but adverse severe effect that usually appears in people with liver, renal, or heart problems. Reporting abnormal symptoms such as extreme exhaustion, breathing problems, muscle pain, or abdominal discomfort should be done promptly.
- If one experiences allergic reactions such as skin rash, itching, swelling, or shortness of breath, discontinue the medication and seek medical attention.
Alcohol Warning
It is unsafe to consume Glimepiride+ Metformin with alcohol.
Breast Feeding Warning
When taking Glimepiride+ Metformin, avoid nursing the child since this medication may enter into the breast milk.
Pregnancy Warning
It is not recommended during pregnancy as it may harm the unborn baby.
Food Warning
Avoid excessive intake of high-sugar or high-fat foods. Take low fat and a low sugar diet.
The adverse reactions related to Glimepiride+ Metformin can be categorized as: -
- Common Adverse Effects: Hypoglycemia, gastrointestinal disturbances
- Less Common Adverse Effects: Vitamin B12 deficiency, skin reactions
- Rare Adverse Effects: Lactic Acidosis, blood disorders, liver Function Abnormalities.
The clinically relevant drug interactions of Glimepiride + metformin are briefly summarized here:
- Drug-Drug Interaction: Glimepiride + Metformin may interact with calcium channel blockers (verapamil), antacids (cimetidine), HIV/AIDS medications (dolutegravir), heart-related medications (ranolazine), anticancer medications (vandetanib, crizotinib, olaparib), antifungals (fluconazole, miconazole), water pills (acetazolamide), antidiabetic medication (insulin), and anticonvulsants (phenytoin).
- Drug-Food Interaction: Alcohol and metformin together may have interactions. Alcohol use should, therefore, be avoided while taking Glimepiride and metformin as it may raise the risk of lactic acidosis, which is the accumulation of lactic acid in the body.
- Interaction between Drug and Disease: Before using Glimepiride + metformin, inform the physician that you have severe infections, uncontrolled diabetes, lactic acidosis or ketoacidosis (an accumulation of ketone bodies in the blood), dehydration, or issues with your liver or kidneys.
The most common side effects of Glimepiride+ Metformin include:
- Headache
- Hypoglycemia (low blood glucose level)
- Nausea
- Diarrhea
- Stomach pain
- Vomiting
- Metallic taste
Glimepiride+ Metformin should be prudent in the following group of special populations.
- Pregnancy
Glimepiride: Pregnancy Category C: Use caution if the benefits outweigh the risks.
There are no adequate and well-controlled studies of glimepiride in a pregnant population.
Inadequately managed diabetes during pregnancy poses various maternal and fetal risks, including diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, and delivery complications. Poorly controlled diabetes raises the prenatal likelihood of severe birth abnormalities, stillbirth, and morbidity related to excessive fetal growth. Pregnant women with gestational diabetes using sulfonylureas may face an increased risk of adverse neonatal outcomes, such as hospitalization in neonatal intensive care, respiratory distress, hypoglycemia, birth injuries, and macrosomia-related issues. Prolonged severe hypoglycemia in neonates born to mothers taking sulfonylureas at delivery has been reported. Therefore, careful monitoring for hypoglycemia and respiratory distress in neonates is essential. Additionally, glimepiride should be discontinued at least two weeks before planned delivery due to documented cases of severe neonatal hypoglycemia associated with its use. Dosage adjustments are crucial during pregnancy and the postpartum period.
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.
- Nursing Mothers
Glimepiride: Glimepiride should not be taken by nursing mothers to avoid potential consumption through breast milk and potential harm to the infant. If required, the patient needs to discontinue nursing or switch to insulin.
Metformin: In nursing rats, metformin excretes into the milk. Since there is no comparable human data, a choice should be made, either stopping metformin or nursing while considering the mother's need for the chemical.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
- Geriatric Use
The safety and effectiveness of Glimepiride+ Metformin in elderly individuals should be carefully considered because of their changed pharmacokinetics and higher risk of hypoglycemia. Glycemic control can be optimized, and side effects reduced by carefully monitoring renal function and adjusting dosages based on individual response.
Dose Adjustment in Kidney Impairment Patients:
Kidney impairment (Mild to Severe): Not recommended.
Glimepiride with metformin should only be taken in people with normal renal function since metformin is known to be eliminated by the kidneys and because patients with impaired renal function are more likely to experience major adverse medication events.
Dose Adjustment in Hepatic Impairment Patients:
There is no FDA guidance on using Glimepiride+ Metformin in patients with hepatic impairment.
When giving glimepiride + metformin to patients who have inadequate liver function, extreme caution should be used. You should consult with a doctor to determine the appropriate dosage and/or intervals between doses.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Glimepiride+ Metformin.
Overconsumption of Glimepiride+ Metformin could lead to
severe hypoglycemia (very low blood sugar), gastrointestinal disturbances, such as nausea, vomiting, and diarrhoea, and a risk of lactic acidosis.
Management
There is no specific antidote or treatment for excessive intake of Glimepiride + Metformin. However, immediate medical attention is essential. Glimepiride + Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
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. Intravenous glucose administration may be required to correct the low blood sugar levels rapidly.
Activated charcoal may help absorb any remaining medication in the stomach and reduce further absorption.
Hemodialysis may be considered in severe cases to remove the drugs from the bloodstream. Patients should be closely monitored for any signs of lactic acidosis, a rare but potentially life-threatening complication, and treated accordingly.
Pharmacodynamics
Glimepiride: Glimepiride enhances insulin granule production from pancreatic beta cells and increases insulin sensitivity in peripheral tissues, increasing peripheral glucose absorption and lowering plasma blood glucose and glycated haemoglobin (HbA1C) levels. A multicenter, randomized, placebo-controlled clinical trial assessed the efficacy of glimepiride (1-8 mg) as monotherapy titrated over ten weeks to placebo in T2DM participants not managed by diet alone. Fasting plasma glucose (FPG) was reduced by 46 mg/dL, post-prandial glucose (PPG) was reduced by 72 mg/dL, and HbA1c was reduced by 1.4% more than the placebo in this trial. In another randomized study of patients with T2DM who received either a placebo or one of three doses (1, 4, or 8 mg) of glimepiride over 14 weeks, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P 0.001) compared to placebo. The 4- and 8-mg doses of glimepiride were more efficacious than the 1-mg dose; however, the 4-mg dose gave almost maximal antihyperglycemic efficacy.
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.
Pharmacokinetics
Absorption
Glimepiride: Glimepiride is entirely absorbed after oral dosing within 1 hour and has a linear pharmacokinetic profile. Peak plasma concentrations (Cmax) of glimepiride were attained 2- 3 hours after a single oral dose in healthy participants and several oral doses in type 2 diabetes patients. Accumulation does not develop after numerous doses. When glimepiride was administered with meals, the duration to attain Cmax rose by 12%, while the mean and AUC (area under the curve) fell by 8 to 9%, respectively. In a pharmacokinetic investigation of Japanese patients with T2DM, Cmax values in once-daily dosages were higher than those in twice-daily doses. Following oral administration, the absolute bioavailability of glimepiride is reported to be complete.
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])
Distribution
Glimepiride: Following dosage, the volume of distribution in healthy participants was 8.8 L (113 mL/kg). Glimepiride has a plasma protein binding rate of more than 99.5%.
Vd: 8.8 L
Protein-bound: 99.5%
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)
Metabolism
Glimepiride: Glimepiride is said to be metabolized in the liver. Following an intravenous or oral dosage, glimepiride undergoes oxidative biotransformation mediated by the CYP2C9 enzyme to create a pharmacologically active primary metabolite, cyclohexyl hydroxymethyl derivative (M1). One or more cytosolic enzymes can further convert M1 to the inactive metabolite carboxyl derivative (M2). M1 preserved roughly one-third of its parent's pharmacologic action in an animal model, with a half-life of 3-6 hours. However, whether M1's glucose-lowering action is therapeutically relevant is still being determined.
Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.
Elimination
Glimepiride: After seven days, when three healthy male individuals were given 14C-glimepiride orally, nearly 60% of the total radioactivity was recovered in the urine. M1 and M2 were responsible for 80-90% of the radioactivity collected in urine. M1:M2 ratio in urine was roughly 3:2 in two participants and 4:1 in one subject. In faeces, around 40% of the total radioactivity was recovered. M1 and M2 accounted for almost 70% of the radioactivity collected in faeces (the M1:M2 ratio was 1:3). No parent medication was found in the urine or faeces. There was no substantial biliary excretion of glimepiride or its M1 metabolite after treatment in subjects.
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.
Therapeutic benefits of a combination of Glimepiride and metformin
- Glimepiride + metformin helps control blood glucose levels in individuals with type 2 diabetes.
- Combining glimepiride and metformin, blood glucose levels can be better controlled throughout the day, minimizing hyperglycemia and enhancing overall glycemic stability.
- Glimepiride + metformin may minimize the risk of side effects associated with higher doses of either medication alone, offering effective glycemic control with potentially fewer adverse reactions.
- Prasanna Kumar KM, Seshadri K, Aravind SR, Deb P, Modi KD, Gopal RA, G VK, Moses CA, Abhyankar M, Revenkar S. Real-World Observational Study of Glimepiride and Metformin Fixed-Dose Combination Along With Insulin in the Management of Type 2 Diabetes Mellitus: Indian Experience. Cureus. 2021 Jan 30;13(1):e13020. doi: 10.7759/cureus.13020. PMID: 33665047; PMCID: PMC7920844.
- Kim HS, Kim DM, Cha BS, Park TS, Kim KA, Kim DL, Chung CH, Park JH, Jang HC, Choi DS. Efficacy of glimepiride/metformin fixed-dose combination vs metformin titration in type 2 diabetic patients inadequately controlled on low-dose metformin monotherapy: A randomized, open-label, parallel-group, multicenter study in Korea. J Diabetes Investig. 2014 Nov;5(6):701-8. doi: 10.1111/jdi.12201. Epub 2014 Mar 16. PMID: 25422771; PMCID: PMC4234234.
- Zhu, H., Zhu, S., Zhang, X. et al. Comparative efficacy of glimepiride and metformin in monotherapy of type 2 diabetes mellitus: meta-analysis of randomized controlled trials. Diabetol Metab Syndr 5, 70 (2013). https://doi.org/10.1186/1758-5996-5-70
- Hollander, P., Liu, J., Hill, J. et al. Ertugliflozin Compared with Glimepiride in the Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study. Diabetes Ther 9, 193–207 (2018). https://doi.org/10.1007/s13300-017-0354-4.
- https://www.centaurpharma.com/downloads/Glimitab-M2018.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020496s027lbl.pdf
- https://www.sanofi.in/dam/jcr:6c1f15ea-d4af-4e93
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448454/
Published on: 10 Nov 2023 10:51 AM GMT