Linagliptin + Metformin
Drug Related WarningLinagliptin + Metformin
Acidosis lactic
- The following outcomes have been reported in postmarketing cases of metformin-associated lactic acidosis: hypotension, hypothermia, and resistant bradyarrhythmias.
- Metformin accumulation might result in lactic acidosis.
- Conditions include acute CHF, hepatic impairment, excessive alcohol use, dehydration, sepsis, renal impairment, and increased risk.
- Metformin-associated lactic acidosis frequently develops gradually, with only vague symptoms such as myalgias, lethargy, respiratory difficulties, somnolence, and abdominal pain.
- Increased blood lactate levels (>5 mmol/litre), anion gap acidosis (without ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels typically >5 mcg/mL are the characteristics of metformin-associated lactic acidosis.
- Metformin-associated lactic acidosis can occur when certain medications are used concurrently (e.g., topiramate, a carbonic anhydrase inhibitor). Other risk factors include renal impairment, age 65 years or older, contrast-enhanced radiography, surgery, other procedures, hypoxic states (e.g., acute congestive heart failure), and hepatic impairment.
- If metformin-associated lactic acidosis is suspected, stop treatment immediately and start general supportive care in a hospital; hemodialysis should begin immediately.
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:
Dipeptidyl Peptidase 4 (DPP-4) Inhibitor, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Germany, France and Australia.
Linagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptidyl Peptidase-IV Inhibitors and biguanide.
The combination of Linagliptin and Metformin is approved for treating type 2 diabetes. When metformin or lifestyle modifications alone cannot achieve glycemic control, this combination of medicines helps lower blood sugar levels in the adults with diabetes mellitus type 2.
Linagliptin has a lengthy half-life, absorbs rapidly, and is mainly eliminated unaltered in the urine. Metformin excretes both unaltered medication and its metabolites in the urine, and its absorption is slower. Combining both provides an effective way of managing type 2 diabetes.
The common side effects of Linagliptin + Metformin are diarrhoea, nausea, vomiting, upset stomach, headache, blocked nose (nasal congestion) and sore throat.
Linagliptin + Metformin is available as tablets for convenient administration.
Linagliptin + Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.
Linagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptidyl Peptidase-IV Inhibitors and biguanide.
Linagliptin: The incretin hormones GLP-1 and GIP (glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide) are inactivated by the enzyme DPP-4, which is inhibited by linagliptin (dipeptidyl peptidase 4, EC 3.4.14.5). The enzyme DPP-4 breaks down these hormones quickly. Incretin hormones work together to maintain glucose homeostasis physiologically. Throughout the day, incretin secretion is at a low baseline level; levels increase as soon as a meal is consumed. GLP-1 and GIP promote insulin production and secretion from pancreatic beta cells in normal and increased blood glucose levels.Additionally, GLP-1 decreases glucagon release from pancreatic alpha cells, lowering the amount of glucose excreted from the liver. Linagliptin causes an extended rise and prolonging of active incretin levels by reversibly and highly effective binding to DPP-4. Linagliptin improves glucose homeostasis via glucose-dependently increasing insulin secretion and decreasing glucagon secretion.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Synergistic Benefits: The combination improves glycemic control by managing numerous aspects of blood sugar management through this dual mode of action. Most of these medications are also weight-neutral, which means that people who are worried about controlling their weight can use them. Combining Linagliptin with Metformin may lower the risk of issues related to the heart. Additionally, certain studies indicate that Linagliptin may have cardiovascular benefits. Together, these treatments make treatment easier, lower the chance of hypoglycemia, and provide overall therapy for diabetes.
Data Onset of action of linagliptin + Metformin typically within 15 to 30 minutes after administration.
Data duration of action of linagliptin + Metformin effects typically lasts about 24 hours after each dose administration.
The Data of Tmax (time to peak concentration) of linagliptin + Metformin occurs within approximately 1 to 4 hours after oral administration
The Data of Cmax of linagliptin + Metformin is typicallyranges from about 45 to 805 ng/mL.
Linagliptin + 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 once daily, generally with a meal.
Linagliptin and Metformin combination is used to treat type 2 diabetes mellitus. This combination is also used in glycemic control and reduces the risk of diabetes-related complications.
Linagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptidyl Peptidase-IV Inhibitors and biguanides.
Linagliptin: Linagliptin helps boost 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.
Linagliptin + Metformin combination provides several therapeutic advantages to patients with type 2 diabetes. It increases the sensitivity and synthesis of insulin, which lowers blood glucose levels. The risk of diabetic complications, including heart disease, renal difficulties, and eye problems, can be effectively decreased by using this combination. It's also been shown to help people with diabetes lose weight and enhance their general quality of life. When combined, linagliptin and metformin provide a practical approach to controlling the disease and any potential risks.
When treatment with both linagliptin + metformin is appropriate, linagliptin + Metformin is indicated as an addition to diet and exercise to improve glycemic control in individuals with type 2 diabetes mellitus.
Important usage restrictions:
- Not for the management of diabetic ketoacidosis or type 1 diabetes.
- It has not been investigated in individuals with a prior pancreatitis diagnosis.
Orally: Linagliptin + Metformin is available as a tablet that can be taken orally. It is recommended that this drug should be taken with a meal for optimal oral administration. Dosing should be individualized to meet the unique requirements of each patient, with an emphasis on both tolerability and effectiveness. When using either prompt-release or extended-release tablets, care should be taken to ensure that the maximum prescribed dose is not exceeded. Gradual dose escalation is advised when commencing prompt-release tablets in order to reduce the potential gastrointestinal adverse effects of metformin. When taking extended-release pills, it's crucial to swallow the entire tablet—not breaking it up, crushing it, dissolving it, or chewing it beforehand. Generally, the extended-release tablet needs to be taken once daily; however, if the dosage is 5 mg/2000 mg, two extended-release tablets containing 2.5 mg of linagliptin and 1000 mg of metformin should be given simultaneously once daily.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Linagliptin + Metformin has various strengths, such as 2.5mg+500mg, 2.5mg + 850 mg, 2.5mg+1000mg or 5mg+1000mg.
Linagliptin + Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
Prompt-release pills
Initial dose (not taking metformin currently): 2.5 mg/500 mg PO BID
Initial dosage (for those on metformin already): Base dosage on existing metformin dosage (e.g., start with 2.5 mg/1000 mg PO BID if taking 1000 mg BID of metformin).
A maximum of 2.5 mg per 1,000 mg BID.
Tablets with extended-release
Adjust the dosage for each patient according on their efficacy and tolerance, making sure they do not exceed above the maximum amount of linagliptin/metformin (5 mg/2000 mg) that is advised for a single day.
Initial dosage: 5 mg/1000 mg PO qDay (not on metformin at this time).
First dosage (on a metformin already): 5 mg of linagliptin taken once daily, along with an equivalent amount of metformin taken once daily.
Change from prompt-release linagliptin/metformin: 5 mg of linagliptin administered daily, and a similar amount of metformin administered daily.
Linagliptin + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Limit consumption of alcohol and excessive drinking, which can lead to hypoglycemia (low blood sugar)
Maintain a balanced diet with a focus on complex carbohydrates, fiber, and lean proteins. Avoid excessive intake of high-sugar or high-fat foods.
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.
The dietary restriction should be individualized as per patient requirements.
Linagliptin + Metformin may be contraindicated in the following conditions:-
- Severe impairment of the kidneys (eGFR < 30 mL/min/1.73 m2)
- Acidity metabolism, including diabetic ketoacidosis.
- Past history of linagliptin-induced hypersensitivity reactions, including anaphylaxis, edema, urticaria, exfoliative skin problems, or bronchial
- Hyperreactivity
- Hypersensitivity to metformin.
- Lactic acidosis: See BLACK BOX warning
- Acute pancreatitis, including fatal pancreatitis, has been shown in postmarketing. As soon as pancreatitis is detected, stop using Metformin and Linigliptin.
- Hypoglycemia: To lessen the chance of hypoglycemia when using insulin or an insulin secretagogue (such as sulfonylurea (SU)), think about reducing the dose of the insulin or secretagogue.
- Postmarketing reports of severe hypersensitivity reactions, including anaphylaxis, oedema, and exfoliative skin problems, have been observed in patients receiving linagliptin (one of the ingredients of linagliptin + Metformin). In such circumstances, stop taking linagliptin and metformin immediately, look for additional possible reasons, set up suitable monitoring and therapy, and start a different diabetic treatment plan.
- Lack of vitamin B12: Metformin may cause a reduction in vitamin B12 levels. Every year, check the hematologic parameters.
- Arthralgia: Patients on DPP-4 inhibitors have been observed to experience severe and disabling arthralgia. Consider as a potential cause for severe joint pain, and stop using the medication if necessary.
- Bullous Pemphigoid: Patients using DPP-4 inhibitors have been reported to experience postmarketing bullous pemphigoid that necessitates hospitalization—instruct patients to report any blisters or erosions that appear. Stop if bullous pemphigoid is suspected. Metformin + linagliptin
- Macrovascular outcomes: Linagliptin + Metformin or any other anti-diabetic medication does not appear to reduce macrovascular risk significantly.
Alcohol Warning
It is unsafe to consume Linagliptin + Metformin with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Sitagliptin + Metformin in breastfeeding.
Pregnancy Warning
There is insufficient scientific evidence regarding the use and safety of Sitagliptin + Metformin in pregnant population.
Food Warning
Avoid excessive intake of high-sugar or high-fat foods.
The adverse reactions related to linagliptin + Metformin can be categorized as:-
- Common Adverse Effects: Hypoglycemia (with sulfonylurea)
- Less Common Adverse Effects: Nasopharyngitis, hypoglycemia (without sulfonylurea), diarrhea
- Rare Adverse Effects: Pancreatitis, allergic reactions, kidney impairment, and liver enzyme elevations.
Reports on Postmarketing
Linagliptin
An acute episode of pancreatitis, which can be fatal
Angioedema, anaphylaxis, and exfoliative skin disorders are examples of hypersensitivity responses.
Severe and disabling arthralgia
Pemphigoid bullous
Rash
oral ulcers and stomatitis.
The rabdomyolysis
Metformin
Liver injury caused by cholestatic, hepatocellular, and mixed hepatocytes.
The clinically relevant drug interactions of linagliptin + Metformin are briefly summarized here:
- Inhibitors of carbonic anhydrase may raise the risk of lactic acidosis. Consider monitoring more often.
- Drugs, including ranolazine, vandetanib, dolutegravir, and cimetidine that decrease metformin clearance may cause more metformin to accumulate. Examine the advantages and disadvantages of using concurrently.
- Metformin's effects on lactate metabolism can be amplified by alcohol. Advise patients not to consume alcohol in excess.
- Potent CYP3A4/P-glycoprotein inducer: When taken together (e.g., rifampin), efficacy may be decreased. It is highly advised to use alternative therapies.
The most common side effects of linagliptin + Metformin include:
- Nausea
- Headache
- Low blood glucose, or hypoglycemia
- Dizziness
- Tremors
Linagliptin + Metformin should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.
There is insufficient evidence for pregnant women to determine the risk of severe birth abnormalities and miscarriage related to the product. The use of metformin during pregnancy has not been linked to a significant increase in the incidence of severe congenital disabilities or miscarriages, while poorly controlled diabetes during pregnancy has risks for both the mother and the fetus.
Maternal risk factors for pre-eclampsia, delivery difficulties, and diabetic ketoacidosis are increased when diabetes is poorly treated during pregnancy. Uncontrolled diabetes raises the chance of severe birth abnormalities, stillbirth, and morbidity associated with macrosomia in fetuses.
Animal data
When Wistar Han rats were given linagliptin at a dose 49 times the 5 mg clinical dose from gestation day 6 to lactation day 21, no negative functional, behavioural, or reproductive consequence was seen in the offspring.
When given orally to the pregnant rats and rabbits, linagliptin penetrates the placenta and enters the fetus.
When given to the pregnant Sprague Dawley rats and rabbits at up to 600 mg/kg/day during the organogenesis period, metformin hydrochloride did not harm development; for the rats and rabbits, this corresponds to exposures of about 2 and 6 times a clinical dose of 2000 mg, based on body surface area (mg/m2).
- Nursing Mothers
Although linagliptin is found in rat milk, there is no evidence about the product's presence in the human milk, its effects on breastfed infants, or its effects on milk production. There is evidence from a few studies that metformin can be found in human milk. However, the effects of metformin on breastfed infants and milk production still need to be better understood. As a result, the benefits of breastfeeding for development and health should be taken into account, as well as the mother's clinical need for therapy and any potential adverse effects on the child from the mother's underlying condition or treatment.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population (under 18 years)have yet to be established.
- Geriatric Use
Linagliptin + Metformin is safe and effective in the elderly population, and its outcomes are primarily comparable with those of the adult population. To maintain glycemic control, senior individuals may need more frequent monitoring and possible dose modifications since they may be more susceptible to the hypoglycemia effects. Because age-related renal impairment may occur, regular monitoring of renal function is essential.
Dosage adjustment in geriatric patients
Type 2 Diabetes Mellitus
It should only begin in individuals 80 or older if a CrCl measurement shows their renal function is not diminished.
Dose Adjustment in Kidney Impairment Patient:
Before starting metformin, ascertain eGFR.
Lower than 30 mL/min/1.73 m²: Not Recommended eGFR 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, for example).
When taking metformin, if eGFR falls below 45 mL/min/1.73 m², the risks and benefits of continuing medication should be assessed.
Once your eGFR falls to less than 30 mL/min/1.73 m², stop taking metformin.
If renal impairment requires discontinuing combination therapy, linagliptin may be taken as a single entity pill at the same dose of 5 mg daily; patients with renal impairment are not advised to change their linagliptin dosage.
Dosing Considerations
Patients with an eGFR between 30 and 60 mL/minute/1.73 m², those with a past history of liver disease, alcoholism, or heart failure, or those who will receive intra-arterial iodinate contrast should stop taking metformin at the time of or before an iodinated contrast imaging treatment.
Dose Adjustment in Hepatic Impairment Patients:
The use of metformin in those patients with hepatic impairment has been associated with some cases of lactic acidosis. Linagliptin + Metformin is not recommended in patients with hepatic impairment.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Linagliptin + Metformin.
Overconsumption of Linagliptin+ Metformin could lead to severe hypoglycemia with symptoms like severe hypoglycemia (low blood sugar) with symptoms like confusion, dizziness, shakiness, sweating, rapid heartbeat, and loss of consciousness.
Management
There is no specific antidote or treatment for excessive intake of Linagliptin + Metformin. However, immediate medical attention is essential. Linagliptin+ Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
To raise blood sugar levels rapidly, intravenous (IV) glucose is administered to the patient. Dextrose solutions, such as 10% dextrose, are commonly used to provide a quick source of glucose.
Supportive care may include the management of symptoms, such as providing fluids and electrolytes if necessary and administering antiemetic medications for nausea and vomiting. In cases of severe hypoglycemia, medical professionals will closely monitor and manage the patient until their condition stabilizes.
Pharmacodynamics
Linagliptin: The concentration of incretin hormones increases due to the ligand's reversible binding to DPP-4. Optimal control of glucose homeostasis is achieved by linagliptin's glucose-dependent increase in insulin secretion and decrease in glucagon secretion. Linagliptin binds specifically to DPP-4 and suppresses DPP-4 activity in vitro at doses close to those used in therapeutic exposures but not DPP-8 or DPP-9.
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
Linagliptin: Linagliptin has an estimated 30% absolute bioavailability. A high-fat meal co-administered with linagliptin resulted in a 2-hour delay in reaching Cmax and a 15% reduction in Cmax, but no effect on AUC 0-72h was seen. Lintagliptin can be taken with or without food because there shouldn't be any clinically significant effects from Cmax and Tmax variations.
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
Linagliptin: A single 5 mg intravenous dosage of linagliptin causes about 1,110 litres of mean apparent volume of distribution at steady-state in healthy people due to tissue binding, demonstrating linagliptin's broad tissue distribution. With increasing linagliptin concentration, the plasma protein binding of linagliptin decreases, from 99% at one nmol/l to 75-89% at 30 nmol/l, showing saturation of binding to DPP-4. When DPP-4 is wholly saturated at high doses, 70–80% of linagliptin is bound to proteins other than DPP-4 in the plasma, allowing 30–20% unbound.
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
Linagliptin: A 10 mg oral dosage of [14C] linagliptin eliminated 5% of the radioactivity in urine. The metabolism only has a little impact on how quickly linagliptin is excreted. One major metabolite was shown to be pharmacologically inactive. It hence did not contribute to the plasma DPP-4 inhibitory action of linagliptin, although at steady-state having a relative exposure of 13.3% of linagliptin.
Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.
Elimination
Linagliptin: Within four days after administering an oral dosage of [14C] linagliptin, 85% of the radioactivity was removed, with the remaining 15% passing through urine or faeces.
An average of 70 ml/min of renal clearance was measured at a steady state.
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 Linagliptin + Metformin
- This combination helps lower elevated blood sugar levels.
- Linagliptin increases the levels of incretin hormones, which stimulate insulin release while inhibiting glucagon secretion. Metformin lowers glucose production in the liver and enhances insulin sensitivity in the muscles, leading to better overall glycemic control.
- Linagliptin + Metformin is typically considered weight neutral. This benefits individual looking to maintain or lose weight as part of their diabetes management plan.
- Ross SA, et al. Linagliptin plus metformin in the patients with newly diagnosed type 2 diabetes and marked hyperglycemia. Postgrad Med. 2016 Nov;128(8):747-754. Doi 10.1080/00325481.2016.1238280. Epub 2016 Sep 29. PMID: 27684308.
- Haak T, Meinicke T, et al. Initial combination of linagliptin and metformin in the patients with type 2 diabetes: The efficacy and safety in a randomized, double-blind 1-year extension study. Int J Clin Pract. 2013 Dec;67(12):1283-93. doi: 10.1111/ijcp.12308. Epub 2013 Oct 9. PMID: 24118640; PMCID: PMC4282285.
- Mu Y, Pan C, et al. Efficacy and safety of linagliptin/metformin single-pill combination as initial therapy in drug-naïve Asian patients with type 2 diabetes. Diabetes Res Clin Pract. 2017 Feb;124:48-56. doi: 10.1016/j.diabres.2016.11.026. Epub 2016 Dec 5. PMID: 28088030.
- Durán-Garcia S, Lee J, Yki-Järvinen H, Rosenstock J, Hehnke U, Thiemann S, Patel S, Woerle HJ. Efficacy and the safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes. Diabet Med. 2016 Jul;33(7):926-33. Doi: 10.1111/dme.13041. Epub 2016 Jan 7. PMID: 26605991.
- Koliaki C, Doupis J. Linagliptin/Metformin fixed-dose combination treatment: a dual attack to type 2 diabetes pathophysiology. Adv Ther. 2012 Dec;29(12):993-1004. doi: 10.1007/s12325-012-0067-z. Epub 2012 Nov 23. PMID: 23184570.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201281S014S018lbl.pdf
- https://dailymed.nlm.nih.gov/dailymed/lookup.cfm
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284079/
- https://www.cadth.ca/linagliptin-metformin
Published on: 28 Oct 2023 12:16 PM GMT